WO2024097598A1 - Triazines utiles comme inhibiteurs de la protéine réceptrice de type nod 3 - Google Patents

Triazines utiles comme inhibiteurs de la protéine réceptrice de type nod 3 Download PDF

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WO2024097598A1
WO2024097598A1 PCT/US2023/077986 US2023077986W WO2024097598A1 WO 2024097598 A1 WO2024097598 A1 WO 2024097598A1 US 2023077986 W US2023077986 W US 2023077986W WO 2024097598 A1 WO2024097598 A1 WO 2024097598A1
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triazin
methyl
trifluoromethyl
alkyl
pyrrolo
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PCT/US2023/077986
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English (en)
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Chen CHENG
Donna A. A. W. HAYES
Rohan Rajiv Merchant
Essam Metwally
Anilkumar G. Nair
Akash PATEL
Ning Qi
Brandon M. Taoka
Maoqun TIAN
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Merck Sharp & Dohme Llc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • BACKGROUND Inflammasomes function as central signalling hubs of the innate immune system. They are multi-protein complexes assembled after activation of intracellular pattern recognition receptors (PRRs) by a variety of pathogen-associated molecular patterns (PAMPs) or danger- associated molecular patterns (DAMPs).
  • PRRs pattern recognition receptors
  • PAMPs pathogen-associated molecular patterns
  • DAMPs danger- associated molecular patterns
  • inflammasomes can be formed by nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and Pyrin and HIN200-domain-containing proteins (Van Opdenbosch N and Lamkanfi M. Immunity, 2019 Jun 18;50(6):1352-1364).
  • NOD nucleotide-binding oligomerization domain
  • NLRs nucleotide-binding oligomerization domain
  • HIN200-domain-containing proteins Van Opdenbosch N and Lamkanfi M. Immunity, 2019 Jun 18;50(6):1352-1364.
  • Inflammasome activation triggers a cascade of events that releases pro- inflammatory cytokines, and promotes an inflammatory form of cell death called pyroptosis induced by the activation of Gasdermin.
  • Pyroptosis is a unique form of inflammatory cell death that leads to the release of not only cytokines but also other intracellular components that promote a broader immune
  • inflammasome activation is a major regulator of the inflammatory cascade.
  • the (NOD)-like receptor protein 3 (NLRP3) inflammasome is the most well-studied of all the inflammasomes. NLRP3 can be activated by numerous stimuli including environmental crystals, pollutants, host-derived DAMPs and protein aggregates (Tartey S and Kanneganti TD. Immunology, 2019 Apr;l56(4):329-338).
  • Danger- associated molecular patterns that engage NLRP3 include uric acid and cholesterol crystals that cause gout and atherosclerosis, amyloid-P fibrils that are neurotoxic in Alzheimer's disease, and asbestos particles that cause mesothelioma (Kelley et al., Int J Mol Sci, 2019 Jul 6;20(13)). Additionally, NLRP3 is activated by infectious agents, such as vibrio cholerae, fungal pathogens, such as Aspergillus Jumigatus and Candida albicans, adenoviruses, influenza A virus and SARS-CoV-2 (Tartey and Kanneganti, 2019 (see above); Fung et al.
  • infectious agents such as vibrio cholerae, fungal pathogens, such as Aspergillus Jumigatus and Candida albicans, adenoviruses, influenza A virus and SARS-CoV-2 (Tartey and Kanneganti, 2019 (see above); Fung et
  • the NOD-like receptor protein 3 is a protein-coding gene that encodes a protein consisting of a N- terminal pyrin domain, a nucleotide-binding site domain (NBD), and a leucine-rich repeat (LRR) motif on the C-terminal (Inoue et al., Immunology, 2013, 139, 11-18; Sharif et al., Nature, 2019 Jun; 570(7761):338-343).
  • NLRP3 In response to sterile inflammatory danger signals PAMPs or DAMPs, NLRP3 interacts with the adaptor protein, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and with the protease caspase-1 to form the NLRP3 inflammasome.
  • ASC caspase recruitment domain
  • procaspase-1 Upon activation, procaspase-1 undergoes autoproteolysis and cleaves gasdermin D (Gsdmd) to produce the N-terminal Gsdmd molecule that leads to pore-formation in the plasma membrane and results in a lytic form of cell death called pyroptosis.
  • Gsdmd gasdermin D
  • caspase-1 cleaves the pro-inflammatory cytokines pro-IL-I ⁇ and pro-IL-18 to allow release of its biological active form (Kelley et al., 2019 - see above).
  • the NLRP3 inflammasome activation results in the release of the inflammatory cytokines IL-l ⁇ (interleukin-I ⁇ ) and IL-18 (interleukin-18), which when dysregulated can lead to a number of diseases.
  • Dysregulation of the NLRP3 inflammasome or its downstream mediators are associated with numerous immune diseases, inflammatory diseases, auto-immune diseases and auto- inflammatory diseases.
  • Activation of the NLRP3 inflammasome has been linked to the following diseases and disorders: Cryopyrin-associated Periodic Syndromes; sickle cell disease; systemic lupus erythematosus; allodynia; graft versus host disease; hepatic disorders including non- alcoholic steatohepatitis (NASH), chronic liver disease, viral hepatitis, alcoholic steatohepatitis, and alcoholic liver disease; inflammatory bowel diseases including Crohn's disease and ulcerative colitis; inflammatory joint disorders including gout, pseudogout, arthropathy, osteoarthritis, rheumatoid arthritis; additional rheumatic diseases including dermatomyositis, Still’s disease, and juvenile idiopathic arthritis.
  • Cryopyrin-associated Periodic Syndromes Cryopyrin-associated Periodic Syndromes
  • sickle cell disease systemic lupus erythematosus
  • allodynia graft versus
  • kidney related diseases including hyperoxaluria, lupus nephritis, hypertensive nephropathy, hemodialysis related inflammation, diabetic nephropathy,anddiabetic kidney disease and other inflammatory diseases
  • hyperoxaluria lupus nephritis
  • hypertensive nephropathy hemodialysis related inflammation
  • diabetic nephropathy anddiabetic kidney disease and other inflammatory diseases
  • neuroinflammation-related disorders such as brain infection, acute injury, multiple sclerosis, amyotrophic lateral sclerosis and additional neurodegenerative diseases such as Parkinsons and Alzheimer's disease have also been linked to NLRP3 inflammasome activation (Sarkar et al., NPJ Parkinsons Dis, 2017 Oct 17;3:30).
  • Cardiovascular and metabolic disorders such as atherosclerosis, type I and type II diabetes and diabetes complications including nephropathy and retinopathy, peripheral artery disease, acute heart failure and hypertension have been associated to NLRP3 (Ridker et al., CANTOS Trial Group.
  • NLRP3 associated skin diseases include wound healing and scar formation; inflammatory skin diseases such as acne, atopic dermatitis, hidradenitis suppurativa and psoriasis (Kelly et al., Br J Dermatol, 2015 Dec;l 73(6)).
  • NLRP3 inflammasome activity has also been linked to respiratory conditions such as asthma, sarcoidosis, acute respiratory distress syndrome, Severe Acute Respiratory Syndrome (SARS) (Nieto-Torres et al., Virology, 2015 Nov;485:330-9)); and ocular diseases including age-related macular degeneration (AMD) and diabetic retinopathy (Doyle et al., Nat Med, 2012 May;18(5):791-8).
  • SARS Severe Acute Respiratory Syndrome
  • Cancers linked to NLRP3 include myeloproliferative neoplasms, leukemias, myelodysplastic syndromes, myelofibrosis, lung cancer and colon cancer (Ridker et al., Lancet, 2017 Oct 21;390(10105): 1833-1842; Derangere et al., Cell Death Differ.2014 Dec;21(12): 1914-24; Basiorka et al., Lancet Haematol, 2018 Sep;5(9): e393-e402, Zhang et al., Hum Immunol, 2018 Jan;79(1):57-62). Immune diseases and inflammatory disorders are typically difficult to diagnose or treat efficiently and effectively.
  • NLRP3 inhibitors are disclosed in the following publications: Nat.2022, 1; Cell.2021, 184, 1; J. Mol. Biol.2021, 433, 167308; J. Med. Chem.2021, 64, 101; Nat. Chem. Biol.2019, 15, 556; Nat.2019, 570, 338; Nat. Chem.
  • NLRP3 inhibitors including WO 2021/239885, WO 2021/209552, WO 2021/209539, WO 2021/193897, WO 2020/018975, WO 2020/037116, WO 2020/021447, WO 2020/010143, WO 2019/079119, WO 2019/0166621, WO 2019/121691, WO 2019/034696, WO 2019/034697, WO 2019/034693, WO 25602 2019/034692, WO 2019/034690, WO 2019/034688, WO 2019/034686, WO 2019/008025, WO 2019/008029, WO 2019/023145, WO 2019/023147, WO 2019/025467, WO 2018/167468, WO 2018/015445, WO 2017/184746, WO 2017/184735, WO 2017/184623, WO 2017/184604, WO 2017/184624, WO 2017/140778,
  • novel compounds of structural formula I are inhibitors of NOD- like receptor protein 3 (NLRP3) and may be useful in the treatment and prevention of diseases, disorders and conditions mediated by NLRP3 such as, but not limited to, gout, pseudogout (chondrocalcinosis), cryopyrin-associated periodic syndromes (CAPS), NASH, fibrosis, heart failure, idiophathic pericarditis, atopic dermatitis, inflammatory bowel disease, Alzheimer’s Disease, Parkinson’s Disease and traumatic brain injury.
  • pharmaceutical compositions comprising the compounds of structural formula I and a pharmaceutically acceptable carrier.
  • the present disclosure also relates to methods for the treatment, management, prevention, alleviation, amelioration, suppression or control of disorders, diseases, and conditions that may be responsive to inhibition of the NLRP3 receptor in a subject in need thereof by administering the compounds and pharmaceutical compositions of the present disclosure.
  • the present disclosure also relates to the use of compounds of the present disclosure for manufacture of a medicament useful in treating diseases, disorders and conditions that may be responsive to the inhibition of the NLRP3 receptor.
  • the present disclosure is also concerned with treatment or prevention of these diseases, disorders and conditions by administering the compounds of the present disclosure in combination with a therapeutically effective amount of another agent that may be useful to treat the disease, disorder and condition. Further disclosed are processes for preparing the compounds of structural formula I.
  • novel compounds of structural formula I Y X R 2 R 1 or a pharmaceutically acceptable salt
  • X is selected from the group: (1) CR 3 , and (2) N
  • Y is selected from the group: (1) CR 4 , and (2) N, provided that one of X and Y is N
  • R 1 is selected from the group: ( 1) -C 3-12 cycloalkyl, (2) -C 3-12 cycloalkenyl, and (3) -C 2-12 cycloheteroalkyl, wherein R 1 is unsubstituted or substituted with one to five substituents selected from R a
  • R 2 is selected from the group: (1) aryl, and (2) heteroaryl, wherein R 2 is unsubstituted or substituted with one to five substituents selected from R b
  • R 3 is selected from the group: (1) hydrogen, ( 2) -C 1-6 alkyl, (3) -C 3-6 cycloalkyl, (4) -C 2-6 cyclohe
  • X is selected from the group: CR 3 , and N.
  • X is CR 3 .
  • X is N.
  • Y is selected from the group: CR 4 , and N, provided that one of X and Y is N.
  • Y is N, provided that X is CR 3 .
  • Y is N.
  • Y is CR 4 , provided that X is N. In another embodiment, Y is CR 4 .
  • R1 is selected from the group: -C 3-12 cycloalkyl, -C 3- 12 cycloalkenyl, and -C 2-12 cycloheteroalkyl, wherein R1 is unsubstituted or substituted with one to five substituents selected from R a .
  • R1 is selected from the group: -C 3-12 cycloalkyl, and -C 2- 12 cycloheteroalkyl, wherein R 1 is unsubstituted or substituted with one to five substituents selected from R a .
  • R 1 is unsubstituted or substituted with one to four substituents selected from R a . In another subclass of this class, R 1 is unsubstituted or substituted with one to three substituents selected from R a .
  • R1 is -C 3-12 cycloalkyl, wherein R1 is unsubstituted or substituted with one to five substituents selected from R a . In a class of this embodiment, R 1 is unsubstituted or substituted with one to four substituents selected from R a . In another class of this embodiment, R 1 is unsubstituted or substituted with one to three substituents selected from R a .
  • R1 is -C 3-12 cycloalkenyl, wherein R1 is unsubstituted or substituted with one to five substituents selected from R a .
  • R 1 is unsubstituted or substituted with one to four substituents selected from R a .
  • R 1 is unsubstituted or substituted with one to three substituents selected from R a .
  • R1 is -C 2-12 cycloheteroalkyl, wherein R1 is unsubstituted or substituted with one to five substituents selected from R a .
  • R 1 is unsubstituted or substituted with one to four substituents selected from R a . In another class of this embodiment, R 1 is unsubstituted or substituted with one to three substituents selected from R a .
  • R 1 is selected from the group: pyrrolidine, piperidine, piperazine, morpholine, oxazepine, hexahydropyrrolo[3,4-b]pyrrole, octahydro-1H-pyrrolo[2,3- c]pyridine, octahydro-1H-pyrrolo[3,4-b]pyridine, octahydro-2H-pyrrolo[2,3-c]pyridine, octahydro-3H-pyrrolo[2,3-c]pyridine, octahydro-1H-indole, octa-hydro-2H-imidazo[4,5- c]pyridine, octahydrocyclopenta[b]pyrrole, octahydrocyclo-penta[c]pyrrole, octahydro-2H- pyrido[3,4-d][1,3]oxazine
  • R 1 is unsubstituted or substituted with one to four substituents selected from R a . In another subclass of this class, R 1 is unsubstituted or substituted with one to three substituents selected from R a . In another class of this embodiment, R 1 is octahydro-1H-pyrrolo[2,3-c]pyridine, wherein R 1 is unsubstituted or substituted with one to five substituents selected from R a . In a subclass of this class, R 1 is unsubstituted or substituted with one to four substituents selected from R a .
  • R 1 is unsubstituted or substituted with one to three substituents selected from R a .
  • R 1 is 6-methyl-octahydro-1H- pyrrolo[2,3-c]pyridine.
  • R 2 is selected from the group: aryl, and heteroaryl, wherein R 2 is unsubstituted or substituted with one to five substituents selected from R b .
  • R 2 is unsubstituted or substituted with one to four substituents selected from R b .
  • R 2 is unsubstituted or substituted with one to three substituents selected from R b .
  • R 2 is selected from the group: phenyl, pyridine, benzothiophene, and benzofuran, wherein R 2 is unsubstituted or substituted with one to five substituents selected from R b .
  • R 2 is unsubstituted or substituted with one to four substituents selected from R b .
  • R 2 is 25602 unsubstituted or substituted with one to three substituents selected from R b .
  • R 2 is unsubstituted.
  • R 2 is substituted with one to three substituents selected from R b .
  • R 2 is selected from the group: aryl, and heteroaryl, wherein R 2 is unsubstituted or substituted with one to five substituents selected from R b .
  • R 2 is unsubstituted or substituted with one to four substituents selected from R b .
  • R 2 is unsubstituted or substituted with one to three substituents selected from R b .
  • R 2 is selected from the group: phenyl, pyridine, and benzofuran, wherein R 2 is unsubstituted or substituted with one to five substituents selected from R b .
  • R 2 is unsubstituted or substituted with one to four substituents selected from R b . In another subclass of this class, R 2 is unsubstituted or substituted with one to three substituents selected from R b . In another subclass of this class, R 2 is unsubstituted. In another subclass of this class, R 2 is substituted with one to three substituents selected from R b . In another embodiment, R 2 is heteroaryl, wherein R 2 is unsubstituted or substituted with one to five substituents selected from R b . In a class of this embodiment, R 2 is unsubstituted or substituted with one to four substituents selected from R b .
  • R 2 is unsubstituted or substituted with one to three substituents selected from R b .
  • R 2 is selected from the group: pyridine, benzothiophene, and benzofuran, wherein R 2 is unsubstituted or substituted with one to five substituents selected from R b .
  • R 2 is unsubstituted or substituted with one to four substituents selected from R b .
  • R 2 is unsubstituted or substituted with one to three substituents selected from R b .
  • R 2 is unsubstituted.
  • R 2 is substituted with one to three substituents selected from R b .
  • R 2 is heteroaryl, wherein R 2 is unsubstituted or substituted with one to five substituents selected from R b .
  • R 2 is unsubstituted or substituted with one to four substituents selected from R b .
  • R 2 is unsubstituted or substituted with one to three substituents selected from R b .
  • R 2 is selected from the group: pyridine, and benzofuran, wherein R 2 is unsubstituted or substituted with one to five substituents selected from R b .
  • R 2 is unsubstituted or substituted with one to four substituents selected from R b .
  • R 2 is unsubstituted or substituted with one to three substituents selected from R b .
  • R 2 is unsubstituted.
  • R 2 is substituted with one to three substituents selected from R b .
  • R 2 is aryl, wherein R 2 is unsubstituted or substituted with one to five substituents selected from R b .
  • R 2 is unsubstituted or substituted with one to four substituents selected from R b .
  • R 2 is unsubstituted or substituted with one to three substituents selected from R b .
  • R 2 is phenyl, wherein R 2 is unsubstituted or substituted with one to five substituents selected from R b .
  • R 2 is unsubstituted or substituted with one to four substituents selected from R b .
  • R 2 is unsubstituted or substituted with one to three substituents selected from R b .
  • R 2 is unsubstituted.
  • R 2 is substituted with one to three substituents selected from R b .
  • R3 is selected from the group: hydrogen, -C 1-6 alkyl, -C 3- 6 cycloalkyl, -C 2-6 cycloheteroalkyl, -OH, -C 1-6 alkyl-O-C 1-6 alkyl, -O-C 1-6 alkyl, -NReRf, wherein each alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to four substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to three substituents selected from R c .
  • R 3 is selected from the group: h ydrogen, -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 2-6 cycloheteroalkyl, -OH, -O-C 1-6 alkyl, - NR e R f , wherein R 3 is unsubstituted or substituted with one to five substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to four substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to three substituents selected from R c .
  • R3 is selected from the group: hydrogen, -C 1-6 alkyl, -C 3- 6 cycloalkyl, -C 2-6 cycloheteroalkyl, OH, -O-C 1-6 alkyl, and -NReRf, wherein R3 is unsubstituted or substituted with one to five substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to four substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to three substituents selected from R c .
  • R3 is selected from the group: hydrogen, -C 1-6 alkyl, -C 3- 6 cycloalkyl, and -O-C 1-6 alkyl, wherein each R3 is unsubstituted or substituted with one to five substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to four substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to three substituents selected from R c .
  • R3 is selected from the group: hydrogen, -C 1-6 alkyl, OH, -O- C 1-6 alkyl,and -NR e R f , wherein R 3 is unsubstituted or substituted with one to five substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to four substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to three substituents selected from R c .
  • R 3 is selected from the group: hydrogen, -CH 3 , OH, -OCH 3 , and -NH 2 .
  • R3 is selected from the group: hydrogen, -C 1-6 alkyl, -O-C 1- 6 alkyl, and -NR e R f , wherein R 3 is unsubstituted or substituted with one to five substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to four substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to three substituents selected from R c .
  • R3 is selected from the group: hydrogen, -CH 3 , -OCH 3 , and -NH 2 .
  • R 3 is hydrogen.
  • R3 is selected from the group: hydrogen, -C 1-6 alkyl, -O-C 1- 6alkyl, and -NR e R f , wherein R 3 is unsubstituted or substituted with one to five substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to four substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to three substituents selected from R c .
  • R 3 is selected from the group: hydrogen, -CH 3 , -OCH 3 , and -NH 2 .
  • R3 is -C 1-6 alkyl, wherein each alkyl is unsubstituted or substituted with one to five substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to four substituents selected from R c .
  • R 3 is unsubstituted or substituted with one to three substituents selected from R c .
  • R 3 is -CH 3 .
  • R4 is selected from the group: hydrogen, -C 1-6 alkyl, -C 3- 6 cycloalkyl, -C 2-6 cycloheteroalkyl, -OH, -O-C 1-6 alkyl, -C 1-6 alkyl-O-C 1-6 alkyl, and -NReRf, wherein each R 4 is unsubstituted or substituted with one to five substituents selected from R d . In a class of this embodiment, R 4 is unsubstituted or substituted with one to four substituents selected from R d . In another class of this embodiment, R 4 is unsubstituted or substituted with one to three substituents selected from R d .
  • R4 is selected from the group: hydrogen, -C 1-6 alkyl, -C 3- 6 cycloalkyl, -C 2-6 cycloheteroalkyl, -OH, -O-C 1-6 alkyl, -C 1-6 alkyl-O-C 1-6 alkyl, and -NReRf, wherein R 4 is unsubstituted or substituted with one to five substituents selected from R d . In a class of this embodiment, R 4 is unsubstituted or substituted with one to four substituents selected from R d . In another class of this embodiment, R 4 is unsubstituted or substituted with one to three substituents selected from R d .
  • R 4 is selected from the group: hydrogen, -CH 3 , -CHF 2 , -CHF 3 , cyclopropyl, -OH, -OCH 3 , -OCHF 2 , and -NH 2 , wherein R4 is unsubstituted or substituted with one to five substituents selected from R d . In a subclass of this class, R 4 is unsubstituted or substituted with one to four substituents selected from R d . In another subclass of this class, R 4 is unsubstituted or substituted with one to three substituents selected from R d .
  • R4 is selected from the group: hydrogen, -C 1-6 alkyl, -C 3- 6 cycloalkyl, -OH, -O-C 1-6 alkyl, and -NReRf, wherein R4 is unsubstituted or substituted with one to five substituents selected from R d .
  • R 4 is unsubstituted or substituted with one to four substituents selected from R d .
  • R 4 is unsubstituted or substituted with one to three substituents selected from R d .
  • R4 is selected from the group: hydrogen, -CH 3 , -CHF 2 , -CHF 3 , cyclopropyl, -OH, -OCH 3 , -OCHF 2 , and -NH 2 , wherein R4 is unsubstituted or substituted with one to five substituents selected from R d . In a subclass of this class, R 4 is unsubstituted or substituted with one to four substituents selected from R d . In another subclass of this class, R 4 is unsubstituted or substituted with one to three substituents selected from R d .
  • R4 is selected from the group: hydrogen, -CH 3 , -CHF 2 , -CHF 3 , cyclopropyl, -OH, -OCH 3 , - OCHF 2 , and -NH 2 .
  • R4 is selected from the group: hydrogen, -CH 3 , -CHF 2 , cyclopropyl, and -OCH 3 , wherein R4 is unsubstituted or substituted 25602 with one to five substituents selected from R d .
  • R 4 is unsubstituted or substituted with one to four substituents selected from R d .
  • R 4 is unsubstituted or substituted with one to three substituents selected from R d .
  • R4 is selected from the group: hydrogen, -CH 3 , -CHF 2 , cyclopropyl, and - OCH 3 .
  • R4 is selected from the group: hydrogen, -C 1-6 alkyl, -C 3- 6 cycloalkyl, and -O-C 1-6 alkyl, wherein each R4 is unsubstituted or substituted with one to five substituents selected from R d .
  • R 4 is unsubstituted or substituted with one to four substituents selected from R d .
  • R 4 is unsubstituted or substituted with one to three substituents selected from R d .
  • R4 is selected from the group: hydrogen, -CH 3 , -CHF 2 , -CHF 3 , cyclopropyl, - OCH 3 , and -OCHF 2 , wherein each R4 is unsubstituted or substituted with one to five substituents selected from R d .
  • R 4 is unsubstituted or substituted with one to four substituents selected from R d .
  • R 4 is unsubstituted or substituted with one to three substituents selected from R d .
  • R 4 is selected from the group: hydrogen, -CH 3 , -CHF 2 , -CHF 3 , cyclopropyl, -OCH 3 , and -OCHF 2 .
  • R4 is selected from the group: hydrogen, -CH 3 , -CHF 2 , cyclopropyl, and -OCH 3 , wherein each R 4 is unsubstituted or substituted with one to five substituents selected from R d .
  • R 4 is unsubstituted or substituted with one to four substituents selected from R d .
  • R 4 is unsubstituted or substituted with one to three substituents selected from R d .
  • R4 is selected from the group: hydrogen, -CH 3 , -CHF 2 , cyclopropyl, and -OCH 3 .
  • R4 is selected from the group: -C 1-6 alkyl, -C 3-6 cycloalkyl, and -O-C 1-6 alkyl, wherein R4 is unsubstituted or substituted with one to five substituents selected from R d .
  • R 4 is unsubstituted or substituted with one to four substituents selected from R d .
  • R 4 is unsubstituted or substituted with one to three substituents selected from R d .
  • R4 is selected from the group: -CH 3 , -CHF 2 , -CHF 3 , cyclopropyl, -OCH 3 , and -OCHF 2 , wherein R 4 is unsubstituted or substituted with one to five substituents selected from R d .
  • R 4 is unsubstituted or substituted with one to four substituents selected from R d .
  • R 4 is unsubstituted or substituted with one to three substituents selected from R d .
  • R 4 is selected from the group: -CH 3 , -CHF 2 , - CHF 3 , cyclopropyl, -OCH 3 , and -OCHF 2 .
  • R4 is selected from the group: -CH 3 , -CHF 2 , cyclopropyl, and -OCH 3 , wherein R4 is unsubstituted or substituted with one to five substituents selected from R d .
  • R 4 is unsubstituted or substituted with one to four substituents selected from R d .
  • R 4 is unsubstituted or substituted with one to three substituents selected from R d .
  • R 4 is selected from the group: -CH 3 , -CHF 2 , cyclopropyl, and - OCH 3 .
  • R4 is selected from the group: hydrogen, and -C 1-6 alkyl, wherein each R 4 is unsubstituted or substituted with one to five substituents selected from R d .
  • R4 is selected from the group: hydrogen, -CH 3 .and -CHF 2 .
  • R 4 is selected from the group: hydrogen, and -CH 3 .
  • R4 is -C 1-6 alkyl, wherein each alkyl is unsubstituted or substituted with one to five substituents selected from R d .
  • R 4 is unsubstituted or substituted with one to four substituents selected from R d .
  • R 4 is unsubstituted or substituted with one to three substituents selected from R d .
  • R 4 is selected from the group: -CH 3 , -CHF 2 , and - CHF 3 .
  • R4 is selected from the group: -CH 3 , and -CHF 2 .
  • R4 is -CH 3 .
  • R 4 is hydrogen.
  • each R a is independently selected from the group: CN, -OH, oxo, halogen, –S(O) 2 C 1-6 alkyl, -C 1-6 alkyl, -O-C 1-6 alkyl, -C 3-6 cycloalkyl, -C 2- 6 cycloheteroalkyl, aryl, heteroaryl, -C(O)C 1-6 alkyl, –C 1-6 alkyl-aryl, –C 1-6 alkyl-heteroaryl, – C 1-6 alkyl-C 3-6 cycloalkyl, –C 1-6 alkyl-C 2-6 cycloheteroalkyl, -(CH 2 ) p -O-C 1-6 alkyl, –(CH 2 ) p - O-C 3-6 cycloalkyl, —(CH 2 ) p -O-C 1-6
  • R a is 25602 unsubstituted or substituted with one to five substituents selected from: halogen, CF 3 , OH, C 1- 6alkyl, and -OC1-6alkyl.
  • R a is unsubstituted or substituted with one to four substituents selected from: halogen, CF 3 , OH, C 1-6 alkyl, and -OC 1-6 alkyl.
  • R a is unsubstituted or substituted with one to three substituents selected from: halogen, CF3, OH, C1-6alkyl, and -OC1-6alkyl.
  • each R a is independently selected from the group: CN, -OH, oxo, halogen, –S(O) 2 C 1-6 alkyl, -C 1-6 alkyl, -O-C 1-6 alkyl, -C 3-6 cycloalkyl, -C 2- 6 cycloheteroalkyl, aryl, heteroaryl, -C(O)C 1-6 alkyl, –C 1-6 alkyl-aryl, –C 1-6 alkyl-heteroaryl, – C 1-6 alkyl-C 3-6 cycloalkyl, –C 1-6 alkyl-C 2-6 cycloheteroalkyl, -(CH 2 ) p -O-C 1-6 alkyl, –(CH 2 ) p - O-C 3-6 cycloalkyl, –(CH 2 ) p -O-C 2-6 cycloheteroalkyl, –(CH 2 )
  • R a is unsubstituted or substituted with one to five substituents selected from: halogen, CF 3 , OH, C 1-6 alkyl, and -OC 1-6 alkyl.
  • R a is unsubstituted or substituted with one to four substituents selected from: halogen, CF 3 , OH, C 1-6 alkyl, and -OC 1-6 alkyl.
  • R a is unsubstituted or substituted with one to three substituents selected from: halogen, CF3, OH, C 1-6 alkyl, and -OC 1-6 alkyl.
  • each R a is independently selected from the group: CN, -OH, oxo, halogen, –S(O) 2 C 1-6 alkyl, -C 1-6 alkyl, -O-C 1-6 alkyl, -C 3-6 cycloalkyl, -C 2-6 cycloheteroalkyl, - C(O)C 1-6 alkyl, –C 1-6 alkyl-C 3-6 cycloalkyl, –C 1-6 alkyl-C 2-6 cycloheteroalkyl, -(CH 2 ) p -O-C 1- 6 alkyl, –(CH 2 ) p -O-C 3-6 cycloalkyl, –(CH 2 ) p -O-C 2-6 cycloheteroalkyl, -C 1-6 alkyl-S(O) r Rg, - C 1-6 alkyl-N(Rh)C(O)Ri ,
  • R a is unsubstituted or substituted with one to five substituents selected from: halogen, CF 3 , OH, C 1-6 alkyl, and -OC 1-6 alkyl.
  • R a is unsubstituted or substituted with one to four substituents selected from: halogen, CF 3 , OH, C 1-6 alkyl, and -OC 1-6 alkyl.
  • R a is unsubstituted or substituted with one to three substituents selected from: halogen, CF3, OH, C1- 6 alkyl, and -OC 1-6 alkyl.
  • each R a is independently selected from the group: -OH, oxo, halogen, –S(O) 2 C 1-6 alkyl, -C 1-6 alkyl, -O-C 1-6 alkyl, -C 3-6 cycloalkyl, -C(O)C 1-6 alkyl, - (CH 2 ) p -O-C 1-6 alkyl, -C 1-6 alkyl-S(O) r Rg, -C 1-6 alkyl-N(Rh)C(O)Ri , -N(Rh)C(O)Ri , -N(Rh)2, - - a unsubstituted or substituted with one to five substituents selected from: halogen, CF3, OH, C1- 6 alkyl, and -OC 1-6 alkyl.
  • R a is unsubstituted or substituted with one to four substituents selected from: halogen, CF3, OH, C1-6alkyl, and -OC1-6alkyl. In another class of this embodiment, R a is unsubstituted or substituted with one to three substituents selected from: halogen, CF3, OH, C1-6alkyl, and -OC1-6alkyl.
  • each R a is independently selected from the group: -OH, oxo, halogen, –S(O) 2 C 1-6 alkyl, -C 1-6 alkyl, -O-C 1-6 alkyl, -C 3-6 cycloalkyl, -C(O)C 1-6 alkyl, -C 1- 6 alkyl-N(R h )C(O)R i , -N(R h )C(O)R i , -N(R h )2, and -C(O)R i , wherein each R a is unsubstituted or substituted with one to six substituents selected from halogen, CF 3 , OH, C 1-6 alkyl, and -OC 1- 6alkyl.
  • R a is unsubstituted or substituted with one to five substituents selected from: halogen, CF 3 , OH, C 1-6 alkyl, and -OC 1-6 alkyl.
  • R a is unsubstituted or substituted with one to four substituents selected from: halogen, CF3, OH, C1-6alkyl, and -OC1-6alkyl.
  • R a is unsubstituted or substituted with one to three substituents selected from: halogen, CF 3 , OH, C 1- 6alkyl, and -OC1-6alkyl.
  • each R a is independently selected from the group: -OH, oxo, F, -SO 2 CH 3 , -CD 3 , -CH 3 , -CH 2 CH 3 , -CH 2 F, -CF 2 H, -CH 2 OH, - CH(OH)CH 3 , -OCH 3 , cyclopropyl, cyclopropyl-OH, -NH 2 , -N(CH 3 ) 2 , -NHC(O)CH 3 , - CH 2 NHC(O)CH 3 , -C(O)NH 2 , and -C(O)CH 3 .
  • each Ra is independently selected from the group: -OH, oxo, F, -SO 2 CH 3 , -CD 3 , -CH 3 , -CH 2 CH 3 , -CH 2 F, -CF 2 H, -CH 2 OH, -CH(OH)CH 3 , -OCH 3 , cyclopropyl-OH, -NH 2 , -N(CH 3 ) 2 , -NHC(O)CH 3 , - CH 2 NHC(O)CH 3 , -C(O)NH 2 , and -C(O)CH 3 .
  • each R a is independently selected from the group: -OH, oxo, halogen, -C 1-6 alkyl, -O-C 1-6 alkyl, and -C(O)C 1-6 alkyl, wherein each Ra is unsubstituted or substituted with one to six substituents selected from halogen, CF3, OH, C1-6alkyl, and -OC1- 6 alkyl.
  • R a is unsubstituted or substituted with one to five substituents selected from: halogen, CF3, OH, C1-6alkyl, and -OC1-6alkyl.
  • R a is unsubstituted or substituted with one to four substituents selected from: halogen, CF3, OH, C1-6alkyl, and -OC1-6alkyl. In another class of this embodiment, R a is unsubstituted or substituted with one to three substituents selected from: halogen, CF 3 , OH, C 1- 6alkyl, and -OC1-6alkyl.
  • each R a is independently selected from the group: -OH, oxo, halogen, -C 1-6 alkyl, and -O-C 1-6 alkyl, wherein each Ra is unsubstituted or substituted with one to six substituents selected from halogen, CF3, OH, C1-6alkyl, and -OC1-6alkyl.
  • R a is unsubstituted or substituted with one to five substituents selected from: halogen, CF3, OH, C1-6alkyl, and -OC1-6alkyl.
  • R a is unsubstituted or substituted with one to four substituents selected from: halogen, CF3, OH, C1- 6alkyl, and -OC1-6alkyl.
  • R a is unsubstituted or substituted with one to three substituents selected from: halogen, CF3, OH, C1-6alkyl, and -OC1-6alkyl.
  • each R a is independently selected from the group: -OH, oxo, F, -CD 3 , -CH 3 , -CH 2 CH 3 , and -CH(OH)CH 3 .
  • each Ra is independently selected from the group: CN, -OH, oxo, F, -CH 3 , -CH 2 CH 3 , and -CH(OH)CH 3 .
  • each R a is independently selected from the group: halogen and - C 1-6 alkyl, wherein each R a is unsubstituted or substituted with one to six substituents selected from halogen, CF3, OH, C1-6alkyl, and -OC1-6alkyl.
  • R a is unsubstituted or substituted with one to five substituents selected from: halogen, CF 3 , OH, C 1- 6alkyl, and -OC1-6alkyl.
  • R a is unsubstituted or substituted with one to four substituents selected from: halogen, CF 3 , OH, C 1-6 alkyl, and -OC 1-6 alkyl.
  • R a is unsubstituted or substituted with one to three substituents selected from: halogen, CF 3 , OH, C 1-6 alkyl, and -OC 1-6 alkyl.
  • each Ra is independently selected from the group: F, -CD 3 , -CH 3 , -CH 2 CH 3 , and -CH(OH)CH 3 .
  • each R a is independently selected from the group: F, -CH 3 , -CH 2 CH 3 , and -CH(OH)CH 3 .
  • each Ra is independently selected from the group: F and -CH 3 .
  • each R a is -C 1-6 alkyl, wherein each R a is unsubstituted or substituted with one to six substituents selected from halogen, CF 3 , OH, C 1-6 alkyl, and -OC 1- 6alkyl.
  • R a is unsubstituted or substituted with one to five substituents selected from: halogen, CF 3 , OH, C 1-6 alkyl, and -OC 1-6 alkyl.
  • R a is unsubstituted or substituted with one to four substituents selected from: halogen, CF3, OH, C1-6alkyl, and -OC1-6alkyl.
  • R a is unsubstituted or substituted with one to three substituents selected from: halogen, CF 3 , OH, C 1- 6 alkyl, and -OC 1-6 alkyl.
  • each R a is independently selected from the group: -CH 3 , -CD 3 , -CH 2 CH 3 , and -CH(OH)CH 3 .
  • each Ra is independently selected from the group: -CH 3 , -CH 2 CH 3 , and -CH(OH)CH 3 .
  • each R a is -CH 3 .
  • each R b is independently selected from the group: CN, -OH, oxo, halogen, –S(O) 2 C 1-6 alkyl, -C 1-6 alkyl, -O-C 1-6 alkyl, -C 3-6 cycloalkyl, -C 2-6 cycloheteroalkyl, aryl, heteroaryl, –C 1-6 alkyl-aryl, –C 1-6 alkyl-heteroaryl, –C 1-6 alkyl-C 3-6 cycloalkyl, –C 1- 6 alkyl-C 2-6 cycloheteroalkyl, -(CH 2 ) q -O-C 1-6 alkyl, –(CH 2 ) q -O-C 3-6 cycloalkyl, –(CH 2 ) q -O- C 2-6 cycloheteroalkyl, –(CH 2 ) q -O-aryl, –(CH 2
  • Rb is unsubstituted or substituted with one to five substituents selected from: halogen, -OH, CF 3 , OCF 3 , CN, CH 2 CF 3 , CF 2 CH 3 , -C 1-6 alkyl, and -OC 1-6 alkyl.
  • Rb is unsubstituted or substituted with one to four substituents selected from: halogen, -OH, CF 3 , OCF 3 , CN, CH 2 CF 3 , CF 2 CH 3 , -C 1- 6 alkyl, and -OC 1-6 alkyl.
  • Rb is unsubstituted or substituted with one to three substituents selected from: halogen, -OH, CF 3 , OCF 3 , CN, CH 2 CF 3 , CF 2 CH 3 , -C 1-6 alkyl, and -OC 1-6 alkyl.
  • Rb is unsubstituted or substituted with one to six substituents selected from: halogen, and -OH.
  • R b is unsubstituted or substituted with one to six substituents selected from: F, and -OH.
  • R b is unsubstituted or substituted with one to five substituents selected from: halogen, and -OH. In a subclass of this class, R b is unsubstituted or substituted with one to six substituents selected from: F, and -OH. another class of this embodiment, R b is unsubstituted or substituted with one to four substituents selected from: halogen, and -OH. In a subclass of this class, R b is unsubstituted or substituted with one to six substituents selected from: F, and -OH.
  • R b is unsubstituted or substituted with one 25602 to three substituents selected from: halogen, and -OH.
  • R b is unsubstituted or substituted with one to six substituents selected from: F, and -OH.
  • each R b is independently selected from the group: CN, -OH, oxo, halogen, –S(O) 2 C 1-6 alkyl, -C 1-6 alkyl, -O-C 1-6 alkyl, -C 3-6 cycloalkyl, -C 2-6 cycloheteroalkyl, – C 1-6 alkyl-aryl, –C 1-6 alkyl-heteroaryl, –C 1-6 alkyl-C 3-6 cycloalkyl, –C 1-6 alkyl-C 2- 6 cycloheteroalkyl, -(CH 2 ) q -O-C 1-6 alkyl, –(CH 2 ) q -O-C 3-6 cycloalkyl, –(CH 2 ) q -O-C 2- 6 cycloheteroalkyl, -OC 1-6 alkyl-C 3-6 cycloalkyl, -OC 1-6 alkyl-C
  • Rb is unsubstituted or substituted with one to five substituents selected from: halogen, -OH, CF 3 , OCF 3 , CN, CH 2 CF 3 , CF 2 CH 3 , -C 1- 6 alkyl, and -OC 1-6 alkyl.
  • Rb is unsubstituted or substituted with one to four substituents selected from: halogen, -OH, CF 3 , OCF 3 , CN, CH 2 CF 3 , CF 2 CH 3 , -C 1-6 alkyl, and -OC 1-6 alkyl.
  • Rb is unsubstituted or substituted with one to three substituents selected from: halogen, -OH, CF 3 , OCF 3 , CN, CH 2 CF 3 , CF 2 CH 3 , -C 1-6 alkyl, and -OC 1-6 alkyl.
  • R b is unsubstituted or substituted with one to three substituents selected from: halogen, -OH, CF 3 , OCF 3 , CN, CH 2 CF 3 , CF 2 CH 3 , -C 1-6 alkyl, and -OC 1-6 alkyl.
  • R b is unsubstituted or substituted with one to five substituents selected from: halogen, and -OH. In a subclass of this class, R b is unsubstituted or substituted with one to six substituents selected from: F, and -OH. another class of this embodiment, R b is unsubstituted or substituted with one to four substituents selected from: halogen, and -OH. In a subclass of this class, R b is unsubstituted or substituted with one to six substituents selected from: F, and -OH.
  • R b is unsubstituted or substituted with one to three substituents selected from: halogen, and -OH.
  • each R b is independently selected from the group: CN, -OH, oxo, halogen, –S(O) 2 C 1-6 alkyl, -C 1-6 alkyl, -O-C 1-6 alkyl, -C 3-6 cycloalkyl, -C 2-6 cycloheteroalkyl, – C 1-6 alkyl-C 3-6 cycloalkyl, –C 1-6 alkyl-C 2-6 cycloheteroalkyl, -(CH 2 ) q -O-C 1-6 alkyl, –(CH 2 ) q - O-C 3-6 cycloalkyl, –(CH 2 ) q -O-C 2-6 cycloheteroalkyl, -OC 1-6 alkyl-C 3-6 cycl
  • R b is unsubstituted or substituted with one to five substituents selected from: halogen, -OH, CF 3 , OCF 3 , CN, CH 2 CF 3 , CF 2 CH 3 , -C 1-6 alkyl, and -OC 1-6 alkyl.
  • R b is unsubstituted or substituted with one to four substituents selected from: halogen, -OH, CF 3 , OCF 3 , CN, CH 2 CF 3 , CF 2 CH 3 , -C 1-6 alkyl, and -OC 1-6 alkyl.
  • R b is unsubstituted or substituted with one to three substituents selected from: halogen, -OH, CF 3 , OCF 3 , CN, CH 2 CF 3 , CF 2 CH 3 , -C 1-6 alkyl, and -OC 1-6 alkyl.
  • R b is unsubstituted or substituted with one to six substituents selected from: halogen, and -OH.
  • R b is unsubstituted or substituted with one to six substituents selected from: F, and -OH.
  • R b is unsubstituted or substituted with one to five substituents selected from: halogen, and -OH. In a subclass of this class, R b is unsubstituted or substituted with one to six substituents selected from: F, and -OH. another class of this embodiment, R b is unsubstituted or substituted with one to four substituents selected from: halogen, and -OH. In a subclass of this class, R b is unsubstituted or substituted with one to six substituents selected from: F, and -OH. another class of this embodiment, R b is unsubstituted or substituted with one to three substituents selected from: halogen, and -OH.
  • R b is unsubstituted or substituted with one to six substituents selected from: F, and -OH.
  • each R b is independently selected from the group: CN, -OH, oxo, halogen, -C 1-6 alkyl, -O-C 1-6 alkyl, -C 3-6 cycloalkyl, -C 2-6 cycloheteroalkyl, –C 1-6 alkyl-C 3- 6 cycloalkyl, –C 1-6 alkyl-C 2-6 cycloheteroalkyl, -(CH 2 ) q -O-C 1-6 alkyl, -N(Rk)2, and -C(O)RL, wherein each R b is unsubstituted or substituted with one to six substituents selected from halogen, -OH, CF 3 , OCF 3 , CN, CH 2 CF 3 , CF 2 CH 3 ,
  • R b is unsubstituted or substituted with one to five substituents selected from: halogen, -OH, CF 3 , OCF 3 , CN, CH 2 CF 3 , CF 2 CH 3 , -C 1-6 alkyl, and -OC 1-6 alkyl.
  • R b is unsubstituted or substituted with one to four substituents selected from: halogen, -OH, CF 3 , OCF 3 , CN, CH 2 CF 3 , CF 2 CH 3 , -C 1-6 alkyl, and -OC 1-6 alkyl.
  • R b is unsubstituted or substituted with one to three substituents selected from: halogen, -OH, CF 3 , OCF 3 , CN, CH 2 CF 3 , CF 2 CH 3 , -C 1-6 alkyl, and -OC 1-6 alkyl.
  • R b is unsubstituted or substituted with one to six substituents selected from: halogen, and -OH.
  • R b is unsubstituted or substituted with one to six substituents selected from: F, and -OH.
  • R b is unsubstituted or substituted with one to five substituents selected from: halogen, and -OH. In a subclass of this class, R b is unsubstituted or substituted with one to six substituents selected from: F, and -OH. In another class of this embodiment, R b is unsubstituted or substituted with one to four substituents selected from: halogen, and -OH. In a subclass of this class, R b is unsubstituted or substituted with one to six substituents selected from: F, and -OH.
  • R b is unsubstituted or substituted with one to three substituents selected from: halogen, and -OH.
  • R b is unsubstituted or substituted with one to six substituents selected from: F, and -OH.
  • each R b is independently selected from the group: -OH, halogen, -C 1-6 alkyl, -O-C 1-6 alkyl, and -C 3-6 cycloalkyl, wherein each Rb is unsubstituted or substituted with one to six substituents selected from halogen, -OH, CF 3 , OCF 3 , CN, CH 2 CF 3 , CF 2 CH 3 , - C 1-6 alkyl, and -OC 1-6 alkyl.
  • each Rb is independently selected from the group: -OH, F, Cl, -CH 3 , -CF 3 , -OCHF 2 , -OCF 3 , and cyclopropane, wherein each Rb is unsubstituted or substituted with one to six substituents selected from halogen, -OH, CF 3 , OCF 3 , CN, CH 2 CF 3 , CF 2 CH 3 , -C 1-6 alkyl, and -OC 1-6 alkyl.
  • each Rb is independently selected from the group: -OH, F, Cl, -CH 3 , -CF 3 , -OCHF 2 , -OCF 3 , and cyclopropane.
  • R b is unsubstituted or substituted with one to five substituents selected from: halogen, -OH, CF 3 , OCF 3 , CN, CH 2 CF 3 , CF 2 CH 3 , -C 1-6 alkyl, and -OC 1-6 alkyl.
  • Rb is unsubstituted or substituted with one to four substituents selected from: halogen, -OH, CF 3 , OCF 3 , CN, CH 2 CF 3 , CF 2 CH 3 , -C 1- 6 alkyl, and -OC 1-6 alkyl.
  • Rb is unsubstituted or substituted with one to three substituents selected from: halogen, -OH, CF 3 , OCF 3 , CN, CH 2 CF 3 , CF 2 CH 3 , -C 1-6 alkyl, and -OC 1-6 alkyl.
  • Rb is unsubstituted or substituted with one to six substituents selected from: halogen, and -OH.
  • R b is unsubstituted or substituted with one to six substituents selected from: F, and -OH.
  • R b is unsubstituted or substituted with one to five substituents selected from: halogen, and -OH.
  • R b is unsubstituted or substituted with one to six substituents selected from: F, and -OH.
  • R b is unsubstituted or substituted with one to four substituents selected from: halogen, and -OH.
  • R b is unsubstituted or substituted with one to six substituents selected from: F, and -OH.
  • R b is unsubstituted or substituted with one to three substituents selected from: halogen, and -OH.
  • R b is unsubstituted or substituted with one to six substituents selected from: F, and -OH.
  • each R b is independently selected from the group: -OH, halogen, and -C 1-6 alkyl, wherein each Rb is unsubstituted or substituted with one to six substituents selected from halogen, -OH, CF 3 , OCF 3 , CN, CH 2 CF 3 , CF 2 CH 3 , -C 1-6 alkyl, and -OC 1-6 alkyl.
  • R b is unsubstituted or substituted with one to five substituents selected from: halogen, -OH, CF 3 , OCF 3 , CN, CH 2 CF 3 , CF 2 CH 3 , -C 1-6 alkyl, and -OC 1-6 alkyl.
  • R b is unsubstituted or substituted with one to four substituents selected from: halogen, -OH, CF 3 , OCF 3 , CN, CH 2 CF 3 , CF 2 CH 3 , -C 1-6 alkyl, and - OC 1-6 alkyl.
  • Rb is unsubstituted or substituted with one to three substituents selected from: halogen, -OH, CF 3 , OCF 3 , CN, CH 2 CF 3 , CF 2 CH 3 , -C 1-6 alkyl, and -OC 1-6 alkyl.
  • Rb is unsubstituted or substituted with one to six substituents selected from: halogen, and -OH.
  • R b is unsubstituted or substituted with one to six substituents selected from: F, and -OH.
  • R b is unsubstituted or substituted with one to five substituents selected from: halogen, and -OH. In a subclass of this class, R b is unsubstituted or substituted with one to six substituents selected from: F, and -OH. another class of this embodiment, R b is unsubstituted or substituted with one to four substituents selected from: halogen, and -OH. In a subclass of this class, R b is unsubstituted or substituted with one to six substituents selected from: F, and -OH. another class of this embodiment, R b is unsubstituted or substituted with one to three substituents selected from: halogen, and -OH.
  • R b is unsubstituted or substituted with one to six substituents selected from: F, and -OH.
  • Rb is selected from the group: halogen, -OH, and -C 1-6 alkyl.
  • Rb is selected from the group: F, Cl, -OH, -CH 3 , -CF 3 , -OCF 3 , and - OCHF 2 .
  • R b is selected from the group: Cl, -OH, -CH 3 , - CF 3 , and -OCHF 2 .
  • each Rc is independently selected from the group: -C 1-6 alkyl, OH, halogen, and -OC 1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens.
  • halogen is F.
  • R c is selected from the group: -C 1-6 alkyl, OH, and halogen, wherein alkyl is unsubstituted or substituted with one to three halogens.
  • halogen is F.
  • Rc is selected from the group: -C 1-6 alkyl and halogen, wherein alkyl is unsubstituted or substituted with one to three halogens. In a subclass of this class, halogen is F. In another class of this embodiment, Rc is -C 1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens. In a subclass of this class, halogen is F. In another class of this embodiment, R c is halogen. In a subclass of this class, R c is F.
  • each R d is independently selected from the group: -C 1-6 alkyl, OH, halogen, and -OC 1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens.
  • halogen is F.
  • R d is selected from the group: -C 1-6 alkyl, OH, and halogen, wherein alkyl is unsubstituted or substituted with one to three halogens.
  • halogen is F.
  • Rd is selected from the group: -C 1-6 alkyl and halogen, wherein alkyl is unsubstituted or substituted with one to three halogens. In a subclass of this class, halogen is F. In another class of this embodiment, Rd is -C 1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens. In a subclass of this class, halogen is F. In another class of this embodiment, R d is halogen. In a subclass of this class, R d is F. In another embodiment, each R e is independently selected from the group: hydrogen, and -C 1-6 alkyl.
  • Re is -C 1-6 alkyl.
  • R e is hydrogen.
  • each R f is independently selected from the group: hydrogen, and -C 1-6 alkyl.
  • Rf is -C 1-6 alkyl.
  • R f is hydrogen.
  • each Rg is independently selected from the group: -C 1-6 alkyl, - C 3-6 cycloalkyl, -C 2-6 cycloheteroalkyl, and -NReRf, wherein alkyl, cycloalkyl, and cycloheteroalkyl are unsubstituted or substituted with one to three substituents selected from: - CF 3 , halogen, OH and -OC 1-6 alkyl.
  • each Rg is independently 25602 selected from the group: -C 1-6 alkyl, -C 3-6 cycloalkyl, and -NReRf, wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three substituents selected from: -CF 3 , halogen, OH and -OC 1-6 alkyl.
  • each R g is independently selected from the group: -C 1-6 alkyl, and -NR e R f , wherein alkyl is unsubstituted or substituted with one to three substituents selected from: -CF 3 , halogen, OH and -OC 1-6 alkyl.
  • each Rg is -C 1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: -CF 3 , halogen, OH and -OC 1-6 alkyl. In another class of this embodiment, each Rg is -C 1-6 alkyl.
  • each R h is independently selected from the group: hydrogen, - C 1-6 alkyl, -C 3-6 cycloalkyl, and -C 2-6 cycloheteroalkyl, wherein alkyl, cycloalkyl, and cycloheteroalkyl are unsubstituted or substituted with one to three substituents selected from: - CF 3 , halogen, OH and -OC 1-6 alkyl.
  • each Rh is independently selected from the group: hydrogen, -C 1-6 alkyl, and -C 3-6 cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three substituents selected from: -CF 3 , halogen, OH and -OC 1-6 alkyl.
  • each Rh is independently selected from the group: hydrogen, and -C 1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: -CF 3 , halogen, OH and -OC 1-6 alkyl.
  • each R h is independently selected from the group: hydrogen and -CH 3 .
  • each R h is -C 1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: -CF 3 , halogen, OH and -OC 1-6 alkyl.
  • each Rh is -C 1-6 alkyl.
  • each R h is hydrogen.
  • each R i is independently selected from the group: hydrogen, -C 1- 6 alkyl, -C 3-6 cycloalkyl, -C 2-6 cycloheteroalkyl, and -NReRf, wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three substituents selected from: CF 3 , halogen, OH and -OC 1-6 alkyl.
  • each Ri is independently selected from the group: hydrogen, -C 1-6 alkyl, -C 3-6 cycloalkyl, and -NReRf, wherein alkyl, and cycloalkyl are unsubstituted or substituted with one to three substituents selected from: CF 3 , halogen, OH and -OC 1-6 alkyl.
  • each Ri is independently 25602 selected from the group: hydrogen, -C 1-6 alkyl, and -NR e R f , wherein alkyl is unsubstituted or substituted with one to three substituents selected from: CF 3 , halogen, OH and -OC 1-6 alkyl.
  • each R i is -NR e R f .
  • each R i is -NH2.
  • each R i is independently selected from the group: hydrogen, and -C 1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: CF 3 , halogen, OH and -OC 1-6 alkyl.
  • each Ri is -C 1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: CF 3 , halogen, OH and -OC 1-6 alkyl.
  • each Ri is -C 1- 6 alkyl.
  • each R i is hydrogen.
  • each R j is independently selected from the group: -C 1-6 alkyl, - C 3-6 cycloalkyl, -C 2-6 cycloheteroalkyl, and -NReRf, wherein alkyl, cycloalkyl, and cycloheteroalkyl are unsubstituted or substituted with one to three substituents selected from: - CF 3 , halogen, OH and -OC 1-6 alkyl.
  • each R j is independently selected from the group: -C 1-6 alkyl, -C 3-6 cycloalkyl, and -NReRf, wherein alkyl, and cycloalkyl are unsubstituted or substituted with one to three substituents selected from: -CF 3 , halogen, OH and -OC 1-6 alkyl.
  • each Rj is independently selected from the group: -C1-6alkyl, and -NR e R f , wherein alkyl is unsubstituted or substituted with one to three substituents selected from: -CF 3 , halogen, OH and -OC 1-6 alkyl.
  • each R j is -C 1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: -CF 3 , halogen, OH and -OC 1-6 alkyl. In another class of this embodiment, each Rj is -C 1-6 alkyl.
  • each R k is independently selected from the group: hydrogen, - C 1-6 alkyl, -C 3-6 cycloalkyl, and -C 2-6 cycloheteroalkyl, wherein alkyl, cycloalkyl, and cycloheteroalkyl are unsubstituted or substituted with one to three substituents selected from: - CF 3 , halogen, OH and -OC 1-6 alkyl.
  • each Rk is independently selected from the group: hydrogen, -C 1-6 alkyl, and -C 3-6 cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three substituents selected from: -CF 3 , halogen, OH and -OC 1-6 alkyl.
  • each Rk is independently selected from the group: hydrogen, and -C 1-6 alkyl, wherein alkyl is unsubstituted or substituted 25602 with one to three substituents selected from: -CF 3 , halogen, OH and -OC 1-6 alkyl.
  • each Rk is -C 1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: -CF 3 , halogen, OH and -OC 1-6 alkyl.
  • each R k is -C 1-6 alkyl.
  • each R k is hydrogen.
  • each R L is independently selected from the group: hydrogen, - C 1-6 alkyl, -C 3-6 cycloalkyl, -C 2-6 cycloheteroalkyl, and -NReRf, wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three substituents selected from: CF 3 , halogen, OH and -OC 1-6 alkyl.
  • each RL is independently selected from the group: hydrogen, -C 1-6 alkyl, and -NR e R f , wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three substituents selected from: CF 3 , halogen, OH and -OC 1-6 alkyl.
  • each RL is independently selected from the group: hydrogen, and -C 1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: CF 3 , halogen, OH and -OC 1-6 alkyl.
  • each R L is -C 1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: CF 3 , halogen, OH and -OC 1-6 alkyl.
  • each RL is -C 1-6 alkyl.
  • each R L is hydrogen.
  • p is 0, 1, 2, 3, 4, 5 or 6.
  • p is 0, 1, 2, 3, 4, or 5.
  • p is 1, 2, 3, 4, 5 or 6.
  • p is 1, 2, 3, 4 or 5.
  • p is 0, 1, 2, 3, or 4.
  • p is 1, 2, 3, or 4.
  • p is 0, 1, 2, or 3.
  • p is 0, 1, 2, or 3.
  • p is 1, 2, or 3. In another embodiment, p is 0, 1 or 2. In another embodiment, p is 1 or 2. In another embodiment, p is 0. In another embodiment, p is 1. In another embodiment, p is 2. In another embodiment, p is 3. In another embodiment, p is 4. In another embodiment, p is 5. In another embodiment, p is 6. In another embodiment, q is 0, 1, 2, 3, 4, 5 or 6. In another embodiment, q is 0, 1, 2, 3, 4, or 5. In another embodiment, q is 1, 2, 3, 4, 5 or 6. In another embodiment, q is 1, 2, 3, 4 or 5. In another embodiment, q is 0, 1, 2, 3, or 4. In another embodiment, q is 0, 1, 2, or 3. In another embodiment, q is 1, 2, or 3. In another embodiment, q is 1, 2, or 3. In another embodiment, q is 1, 2, or 3. In another embodiment, q is 1, 2, or 3.
  • q is 0, 1 or 2. In another embodiment, q is 1 or 2. In another embodiment, q is 0. In another 25602 embodiment, q is 1. In another embodiment, q is 2. In another embodiment, q is 3. In another embodiment, q is 4. In another embodiment, q is 5. In another embodiment, q is 6. In another embodiment, r is 0, 1 or 2. In another embodiment, r is 1 or 2. In another embodiment, r is 0. In another embodiment, r is 1. In another embodiment, r is 2. In another embodiment, s is 0, 1 or 2. In another embodiment, s is 1 or 2. In another embodiment, s is 0. In another embodiment, s is 1. In another embodiment, s is 2. Also provided are compounds of structural formula Ia: , or a salt thereof.
  • the compound of structural formula I includes the compounds of structural formulas Ia and Ib, and pharmaceutically acceptable salts, hydrates and solvates thereof.
  • Another embodiment relates to compounds of structural formula I wherein: X is N; Y is CR 4 ; R1 is -C 2-12 cycloheteroalkyl, wherein R1 is unsubstituted or substituted with one to five substituents selected from R a ; R 2 is selected from the group: phenyl, pyridine, thiophene, and benzofuran, wherein R 2 is unsubstituted or substituted with one to five substituents selected from R b ; R 4 is selected from the group: 25602 (1) hydrogen, ( 2) -C 1-6 alkyl, (3) -C 3-6 cycloalkyl, and (4) -O-C 1-6 alkyl, wherein each R 4 is unsubstituted or substituted with one
  • Another embodiment relates to compounds of structural formula I wherein: X is N; Y is CR 4 ; R1 is -C 2-12 cycloheteroalkyl, wherein R1 is unsubstituted or substituted with one to five substituents selected from R a ; R 2 is selected from the group: phenyl, pyridine, and benzofuran, wherein R 2 is unsubstituted or substituted with one to five substituents selected from R b ; R 4 is selected from the group: (1) hydrogen, ( 2) -C 1-6 alkyl, (3) -C 3-6 cycloalkyl, and (4) -O-C 1-6 alkyl, wherein each R 4 is unsubstituted or substituted with one to five substituents selected from R d ; and the other substituents as defined above; or a pharmaceutically acceptable salt thereof.
  • Another embodiment relates to compounds of structural formula I wherein: X is N; Y is CR 4 ; R 1 is selected from the group: (1) pyrrolidine, (2) piperidine, 25602 (3) piperazine, (4) morpholine, (5) oxazepine, (6) hexahydropyrrolo[3,4-b]pyrrole, (7) octahydro-1H-pyrrolo[2,3-c]pyridine, (8) octahydro-1H-pyrrolo[3,4-b]pyridine, (9) octahydro-2H-pyrrolo[2,3-c]pyridine, (10) octahydro-3H-pyrrolo[2,3-c]pyridine, (11) octahydro-1H-indole, (12) octahydro-2H-imidazo[4,5-c]pyridine, (13) octahydrocyclopenta[b]pyrrole, (14) octa
  • Another embodiment relates to compounds of structural formula I wherein: X is N; Y is CR 4 ; R 1 is selected from the group: (1) pyrrolidine, (2) piperidine, (3) piperazine, (4) morpholine, (5) oxazepine, (6) hexahydropyrrolo[3,4-b]pyrrole, (7) octahydro-1H-pyrrolo[2,3-c]pyridine, (8) octahydro-1H-pyrrolo[3,4-b]pyridine, (9) octahydro-2H-pyrrolo[2,3-c]pyridine, (10) octahydro-3H-pyrrolo[2,3-c]pyridine, (11) octahydro-1H-indole, (12) octahydro-2H-imidazo[4,5-c]pyridine, (13) octahydrocyclopenta[b]pyrrole, (14) octahydrocycl
  • Another embodiment relates to compounds of structural formula I wherein: X is N; Y is CR 4 ; R1 is -C 2-12 cycloheteroalkyl, wherein R1 is unsubstituted or substituted with one to five substituents selected from R a ; R 2 is aryl, wherein R 2 is unsubstituted or substituted with one to five substituents selected from R b ; R 4 is selected from the group: (1) hydrogen, and ( 2) -C 1-6 alkyl, wherein each R 4 is unsubstituted or substituted with one to five substituents selected from R d ; and the other substituents are as defined above; or a pharmaceutically acceptable salt thereof.
  • Another embodiment relates to compounds of structural formula I wherein: X is N; Y is CR 4 ; R 1 is selected from the group: (1) pyrrolidine, (2) piperidine, (3) piperazine, 25602 (4) morpholine, (5) oxazepine, (6) hexahydropyrrolo[3,4-b]pyrrole, (7) octahydro-1H-pyrrolo[2,3-c]pyridine, (8) octahydro-1H-pyrrolo[3,4-b]pyridine, (9) octahydro-2H-pyrrolo[2,3-c]pyridine, (10) octahydro-3H-pyrrolo[2,3-c]pyridine, (11) octahydro-1H-indole, (12) octahydro-2H-imidazo[4,5-c]pyridine, (13) octahydrocyclopenta[b]pyrrole, (14) octa
  • Illustrative, but non-limiting, examples of compounds that are useful as inhibitors of the NLRP3 are the following compounds: (1) 2-(5-methyl-3-((3aS,7aR)-6-methyloctahydro-1H-pyrrolo[2,3-c]pyridin-1-yl)- 1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol; (2) (3aS,7aR)-1-(6-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-5-methyl-1,2,4- triazin-3-yl)-6-methyloctahydro-1H-pyrrolo[2,3-c]pyridine; (3) 2-(5-methyl-3-((3aR,7aS)-6-methyloctahydro-1H-pyrrolo[2,3-c]pyridin-1-yl)- 1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol; (4) 4-flu
  • Additional illustrative, but non-limiting, examples of compounds that are useful as inhibitors of the NLRP3 are the following compounds: 25602 (1) 2-(5-methyl-3-((3aS,7aR)-6-methyloctahydro-1H-pyrrolo[2,3-c]pyridin-1-yl)- 1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol; (2) (3aS,7aR)-1-(6-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-5-methyl-1,2,4- triazin-3-yl)-6-methyloctahydro-1H-pyrrolo[2,3-c]pyridine; (3) 5-chloro-2-(5-methyl-3-((3aS,7aR)-6-methyloctahydro-1H-pyrrolo[2,3-c]pyridin- 1-yl)-1,2,4-triazin-6-yl)phenol; (4) 2-
  • Additional illustrative, but non-limiting, examples of compounds that are useful as inhibitors of the NLRP3 are the following compounds: (1) 3,4-difluoro-2-(5-methyl-3-((3aS,7aR)-6-methyloctahydro-1H-pyrrolo[2,3- c]pyridin-1-yl)-1,2,4-triazin-6-yl)phenol; (2) 3-fluoro-2-(5-methyl-3-((3aS,7aR)-6-methyloctahydro-1H-pyrrolo[2,3-c]pyridin- 1-yl)-1,2,4-triazin-6-yl)phenol; (3) 6-chloro-3-fluoro-2-(5-methyl-3-((3aS,7aR)-6-methyloctahydro-1H-pyrrolo[2,3- c]pyridin-1-yl)-1,2,4-triazin-6-yl)phenol; (4) 4,5-difluoro
  • stereoisomers including diastereoisomers, enantiomers, epimers, and mixtures of these may also have utility in treating NLRP3 mediated diseases.
  • Synthetic methods for making the compounds are disclosed in the Examples shown below. Where synthetic details are not provided in the examples, the compounds are readily made by a person of ordinary skill in the art of medicinal chemistry or synthetic organic chemistry by applying the synthetic information provided herein. Where a stereochemical center is not defined, the structure represents a mixture of stereoisomers at that center. For such compounds, the individual stereoisomers, including enantiomers, diastereoisomers, and mixtures of these are also compounds of the disclosure.
  • alkyl means saturated carbon chains which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise.
  • alkenyl means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched, or combinations thereof, unless otherwise defined.
  • alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2- butenyl, 2-methyl-2-butenyl, and the like.
  • Alkynyl means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched, or combinations thereof, unless otherwise defined. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.
  • Cycloalkyl means a saturated monocyclic, bicyclic, spirocyclic, fused or bridged carbocyclic ring, having a specified number of carbon atoms.
  • Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • cycloalkyl is-C 3-12 cycloalkyl.
  • cycloalkyl is selected from: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • cycloalkyl is cyclopropyl.
  • Cycloalkenyl means a monocyclic, bicyclic, spirocyclic, fused or bridged carbocyclic ring, having a specified number of carbon atoms with at least one double bond.
  • Examples of cycloalkenyl include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and the like.
  • cycloalkenyl is -C 3-12 cycloalkenyl.
  • Cycloheteroalkyl means a monocyclic, bicyclic, spirocyclic, fused or bridged ring or ring system having a specified number of carbon atoms and containing at least one saturated ring wherein at least one ring heteroatom selected from N, NH, S (including SO and SO 2 ) and O, or with at least one partially unsaturated ring wherein at least one ring heteroatom selected from N, NH, S (including SO and SO 2 ) and O.
  • the cycloheteroalkyl ring may be substituted on the ring carbons and/or the ring nitrogen or sulfur.
  • the cycloheteroalkyl ring may be fused to an aryl or heteroaryl ring.
  • cycloheteroalkyl examples include tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, azetidinyl, piperazinyl, piperidinyl, morpholinyl, oxetanyl and tetrahydropyranyl.
  • C 2-12 cycloheteroalkyl is selected from: pyrrolidine, piperidine, piperazine, morpholine, oxazepine, hexahydropyrrolo[3,4-b]pyrrole, octahydro-1H- pyrrolo[2,3-c]pyridine, octahydro-1H-pyrrolo[3,4-b]pyridine, octahydro-2H-pyrrolo[2,3- c]pyridine, octahydro-3H-pyrrolo[2,3-c]pyridine, octahydro-1H-indole, octahydro-2H- imidazo[4,5-c]pyridine, octahydrocyclopenta[b]pyrrole, octahydrocyclopenta[c]pyrrole, octahydro-2H-pyrido[3,4-d][1,3]oxazin
  • Cycloheteroalkenyl means a monocyclic, bicyclic, spirocyclic, fused, or bridged ring or ring system having a specified number of carbon atoms and containing at least one double bond 25602 and at least one heteroatom selected from N, NH, S (including SO and SO 2 ) and O.
  • Examples of cycloheteroalkenyl include dihydropyran and dihydrofuran, and the like.
  • Aryl means a monocyclic, bicyclic or tricyclic carbocyclic aromatic ring or ring system containing 6-14 carbon atoms, wherein at least one of the rings is aromatic. Examples of aryl include phenyl and naphthyl.
  • aryl is phenyl.
  • Heteroaryl means a monocyclic, bicyclic or tricyclic ring or ring system containing 5- 14 ring atoms and containing at least one ring heteroatom selected from N, NH, S (including SO and SO 2 ) and O, wherein at least one of the heteroatom containing rings is aromatic.
  • heteroaryl examples include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, quinolyl, indolyl, isoquinolyl, quinazolinyl, dibenzofuranyl, and the like.
  • heteroaryl is pyridine or benzofuran. In another embodiment, heteroaryl is pyridine, benzothiophene, or benzofuran. In another embodiment, heteroaryl is pyridine. In another embodiment, heteroaryl is benzofuran. In yet another embodiment, heteroaryl is pyridyl, benzothiophenyl, benzofuranyl or thiophenyl.
  • "Halogen" includes fluorine, chlorine, bromine and iodine. In one embodiment, halogen is fluorine, chorine or bromine. In another embodiment, halogen is fluorine or chlorine. In another embodiment, halogen is chlorine or bromine. In another embodiment, halogen is fluorine or bromine.
  • a squiggly line across a bond in a substituent variable represents the point of attachment. 25602 Under nomenclature used throughout this disclosure, the point of attachment is described first, followed by the terminal portion of the designated side chain.
  • a C 1-5 alkylcarbonylamino C 1-6 alkyl substituent is equivalent to: O - C1-5alkyl - C-NH-C1-6alkyl
  • the various e tc. are to be chosen in conformity with well-known principles of chemical structure and stability. The term shall be deemed to include multiple degrees of substitution by a named substitutent.
  • the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally.
  • independently substituted it is meant that the (two or more) substituents can be the same or different.
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, salts and/or dosage forms which are, using sound medical judgment, and following all applicable government regulations, safe and suitable for administration to a human being or an animal.
  • Compounds of Formula I may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers.
  • the present disclosure is meant to encompass all such isomeric forms of the compounds of Formula I.
  • the independent syntheses of optical isomers and diastereoisomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein.
  • Their absolute stereochemistry may be determined by the X- ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration or sufficient heavy atoms to make an absolute assignment. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated.
  • the separation can be carried out by methods well-known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereoisomeric mixture, followed by separation of the individual diastereoisomers by standard methods, such as fractional crystallization or chromatography.
  • the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
  • the diasteromeric 25602 derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • the racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
  • any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
  • Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
  • Tautomers are defined as compounds that undergo rapid proton shifts from one atom of the compound to another atom of the compound.
  • Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula I.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominately found in nature. Included are all suitable isotopic variations of the compounds of structural formula I.
  • different isotopic forms of hydrogen (H) include protium ( 1 H), deuterium ( 2 H), and tritium ( 3 H).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Tritium is radioactive and may therefore provide for a radiolabeled compound, useful as a tracer in metabolic or kinetic studies.
  • Isotopically-enriched compounds within structural formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • some of the crystalline forms for compounds of structural formula I may exist as polymorphs and as such are intended to be included in the present invention.
  • some of the compounds of structural formula I may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.
  • pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed within the term “pharmaceutically acceptable salt” refer to non-toxic salts of the compounds structural formula I which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
  • Representative salts of basic compounds of structural formula I include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, formic, fumarate, gluceptate, gluconate, glutamate, glycollylars-anilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N- methylglucamine am
  • suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, 25602 cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion-exchange resins such as arginine, betaine, caffeine,
  • esters of carboxylic acid derivatives such as methyl, ethyl, or pivaloyloxymethyl
  • acyl derivatives of alcohols such as O-acetyl, O-pivaloyl, O-benzoyl, and O-aminoacyl
  • esters and acyl groups known in the art for modifying the solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations.
  • prodrug means compounds that are rapidly transformed, for example, by hydrolysis in blood, in vivo to the parent compound, e.g., conversion of a prodrug of Formula I to a compound of Formula I, or to a salt thereof; a thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. Prodrugs of the novel compounds of structural formula I are included. Solvates, and in particular, the hydrates of the compounds of structural formula I are included as well.
  • Compounds of structural formula I are potent inhibitors of Nod-Like Receptor Protein 3 (NLPR3).
  • the compounds, and pharmaceutically acceptable salts thereof, may be efficacious in the treatment of diseases, disorders and conditions that are mediated by the inhibition of Nod- Like Receptor Protein 3 (NLPR3).
  • the present disclosure relates to the treatment or prevention of a disease, disorder or condition mediated by NLRP3 such as inflammation, an auto-immune disease, a cancer, an infection, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a fibrotic disease or fibrosis, a respiratory disease, a kidney disease, a liver disease, an ophthalmic or ocular disease, a skin disease, a lymphatic disease, a rheumatic disease, graft versus host disease, allodynia, or an NLRP3-related disease in a subject that has been determined to carry a germline or somatic non-silent mutation in NLRP3.
  • NLRP3 such as inflammation, an auto-immune disease, a cancer, an infection, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a fibrotic disease or fibrosis, a respiratory disease, a kidney disease, a liver disease, an ophthalmic or
  • the disease, disorder or condition mediated by NLRP3 includes but is not limited to: gout, pseudogout, osteoarthritis, familial cold autoinflammatory syndrome, Muckle-Wells syndrome, neonatal onset multisystem inflammatory disease, diabetes, NASH, sepsis, age related macular degeneration, diabetic retinopathy, liver fibrosis, kidney fibrosis, atherosclerosis, heart failure, peripheral artery disease, myeloproliferative neoplasm, leukemia, myelodysplastic syndrome, myelofibrosis, lung cancer, colon cancer, Parkinson’s disease, Alzheimer’s disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, multiple sclerosis, atopic dermatitis, hidradenitis suppurativa, pericarditis, myocarditis, preeclampsia, dermatomyositis.
  • NLPR3 Nod-Like Receptor Protein 3
  • NLPR3 Nod-Like Receptor Protein 3
  • diseases, disorders or conditions mediated by Nod-Like Receptor Protein 3 also include, but are not limited to, gout, pseudogout, CAPS, NASH, fibrosis, osteoarthritis, atherosclerosis, heart failure, idiophathic pericarditis, myocarditis, atopic dermatitis, hidradenitis suppurativa, inflammatory bowel disease, cancer, Alzheimer’s Disease, Parkinson’s Disease and traumatic brain injury.
  • the condition, disease or disorder is an inflammatory joint disease such as gout, pseudogout, or osteoarthritis.
  • cryopyrin-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, or neonatal onset multisystem inflammatory disease.
  • the metabolic disease is diabetes.
  • the liver disease is NASH.
  • the infection is sepsis.
  • the ophthalmic or ocular disease is age related macular degeneration or diabetic retinopathy.
  • the fibrotic disease is liver fibrosis or kidney fibrosis.
  • the cardiovascular disease is atherosclerosis, heart failure or peripheral artery disease.
  • the cancer is myeloproliferative neoplasm, leukemia, myelodysplastic syndrome, myelofibrosis, lung cancer or colon cancer.
  • the condition, disease or disorder of the central nervous system is Parkinson’s disease, Alzheimer’s disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, or multiple sclerosis.
  • the skin disease is atopic dermatitis or hidradenitis suppurativa (HS).
  • the inflammatory disease is pericarditis or myocarditis.
  • the inflammatory disease is preeclampsia.
  • the rheumatic disease is dermatomyositis.
  • the ocular disease is age related macular degeneration, or diabetic retinopathy.
  • the kidney disease is an acute kidney disease, a chronic kidney disease, or a rare kidney disease.
  • a therapeutically effective amount of a compound of structural formula I, Ia or Ib or a pharmaceutically acceptable salt thereof, to a patient in need of treatment may be treated, managed, prevented, reduced, alleviated, ameliorated or controlled by the administration of a therapeutically effective amount of a compound of structural formula I, Ia or Ib or a pharmaceutically acceptable salt thereof, to a patient in need of treatment.
  • the compounds of structural formulae I, Ia and Ib and pharmaceutically acceptable salts thereof may also be used for the manufacture of a medicament which may be useful for treating, preventing, managing, alleviating, ameliorating or controlling one or more of these conditions, diseases or disorders, including but not limited to: gout, pseudogout, osteoarthritis, familial cold autoinflammatory syndrome, Muckle-Wells syndrome, neonatal onset multisystem inflammatory disease, diabetes, NASH, sepsis, age related macular degeneration, diabetic retinopathy, liver fibrosis, kidney fibrosis, atherosclerosis, heart failure, peripheral artery disease, myeloproliferative neoplasm, leukemia, myelodysplastic syndrome, myelofibrosis, lung cancer, colon cancer, Parkinson’s disease, Alzheimer’s disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, multiple sclerosis, atopic dermatitis, hidradenitis suppurativa, pericarditis
  • Still’s disease juvenile idiopathic arthritis, age related macular degeneration, diabetic retinopathy, acute kidney disease, a chronic kidney disease, or a rare kidney disease.
  • the compounds of structural formulae I, Ia and Ib and pharmaceutically acceptable salts thereof may also be used for the manufacture of a medicament which may be useful for treating, preventing, managing, alleviating, ameliorating or controlling one or more of these conditions, diseases or disorders, including but not limited to: gout, pseudogout, CAPS, NASH, fibrosis, osteoarthritis, atherosclerosis, heart failure, idiophathic pericarditis, myocarditis, atopic dermatitis, hidradenitis suppurativa, inflammatory bowel disease, cancer, Alzheimer’s Disease, Parkinson’s Disease and traumatic brain injury.
  • Preferred uses of the compounds may be for the treatment of one or more of the following diseases by administering a therapeutically effective amount to a patient in need of treatment.
  • the compounds may be used for manufacturing a medicament for the treatment of one or more of these diseases: (1) gout, (2) pseudogout, (3) cryopyrin-associated periodic syndromes, (4) non-alcoholic steatohepatitis, (5) fibrosis, (6) osteoarthritis, (7) atherosclerosis, (8) atopic dermatitis, (9) hidradenitis suppurativa, (10) Alzheimer’s Disease, and (11) Parkinson’s Disease.
  • Treatment of a disease, disorder or condition mediated by NLPR3 or the NLPR3 inflammasome pathway refers to the administration of a compound of structural formula I, Ia or Ib or a pharmaceutically acceptable salt thereof to a subject with the disease, disorder or condition.
  • One outcome of treatment may be reducing the disease, disorder or condition mediated by NLPR3 or the NLPR3 inflammasome pathway.
  • Another outcome of treatment may be alleviating the disease, disorder or condition mediated by NLPR3 or the NLPR3 inflammasome pathway.
  • Another outcome of treatment may be ameliorating the disease, disorder or condition mediated by NLPR3 or the NLPR3 inflammasome pathway.
  • Another outcome of treatment may be suppressing the disease, disorder or condition mediated by mediated by NLPR3 or the NLPR3 inflammasome pathway.
  • Another outcome of treatment may be managing the disease, disorder or condition mediated by NLPR3 or the NLPR3 inflammasome pathway.
  • Another outcome of treatment may be preventing the disease, disorder or condition mediated by NLPR3 or the NLPR3 inflammasome pathway.
  • Prevention of the disease, disorder or condition mediated by NLPR3 or the NLPR3 inflammasome pathway refers to the administration of a compound of structural formula I, Ia or Ib or a pharmaceutically acceptable salt thereof to a subject at risk of the disease, disorder or condition.
  • One outcome of prevention may be reducing the disease, disorder or condition mediated by NLPR3 or the NLPR3 inflammasome pathway in a subject at risk of the disease, disorder or condition. Another outcome of prevention may be suppressing the disease, disorder or condition mediated by NLPR3 or the NLPR3 inflammasome pathway in a subject at risk of the disease, disorder or condition. Another outcome of prevention may be ameliorating the disease, disorder or condition mediated by NLPR3 or the NLPR3 inflammasome pathway in a subject at risk of the disease, disorder or condition. Another outcome of prevention may be alleviating the disease, disorder or condition mediated by NLPR3 or the NLPR3 inflammasome pathway in a subject at risk of the disease, disorder or condition.
  • Another outcome of prevention may be managing the disease, disorder or condition mediated by NLPR3 or the NLPR3 inflammasome pathway in a subject at risk of the disease, disorder or condition.
  • administration of and or “administering a” compound should be understood to mean providing a compound of structural formula I, Ia or Ib or a prodrug of a compound of structural formula I, Ia or Ib or a pharmaceutically acceptable salt of such compound or prodrugto the individual or mammal in need of treatment.
  • the administration of the compound of structural formula I in order to practice the present methods of therapy is carried out by administering an effective amount of the compound of structural formula I to the mammal in need of such treatment or prophylaxis.
  • the need for a prophylactic administration according to the methods described herein is determined via the use of well known risk factors.
  • the effective amount of an individual compound is determined, in the final analysis, by the physician or veterinarian in charge of the case, but depends on factors such as the exact disease to be treated, the severity of the disease and other diseases or conditions from which the patient suffers, the chosen route of administration other drugs and treatments which the patient may concomitantly require, and other factors in the physician's judgment.
  • the usefulness of the present compounds in these diseases or disorders may be demonstrated in animal disease models that have been reported in the literature.
  • Administration and Dose Ranges Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of structural formula I, Ia or Ib.
  • a suitable dosage level will generally be about 0.0001 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • a suitable dosage level may be about 0.001 to 500 mg per kg patient body weight per day. In another embodiment, a suitable dosage level may be about 0.001 to about 250 mg/kg per day. In another embodiment, a suitable dosage level may be about 0.01 to about 250 mg/kg per day. In another embodiment, a suitable dosage level may be about 0.1 to about 100 mg/kg per day. In another embodiment, a suitable dosage level may be about 0.05 to 100 mg/kg per day. In another embodiment, a suitable dosage level may be about 0.1 to 50 mg/kg per day. In another embodiment, a suitable dosage level may be about 0.05 to 0.5 mg/kg per day. In another embodiment, a suitable dosage level may be about 0.5 to 5 mg/kg per day.
  • a suitable dosage level may be about 5 to 50 mg/kg per day.
  • the compositions are preferably provided in the form of tablets containing 0.01 to 1000 mg of the active ingredient, particularly 0.01, 0.025, 0.05, 0.075, 0.1, 0.25, 0.5, 0.75, 1.0, 2.5, 5.0, 7.5, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the compounds may be administered on a regimen of 1 to 8 times per day; preferably, 1 to 4 times a day; more preferably once or twice per day, even more preferably once a day.
  • This dosage regimen may be adjusted to provide the optimal therapeutic response. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
  • the compounds structural formulae I, Ia and Ib may be used in pharmaceutical compositions comprising (a) the compound(s) or pharmaceutically acceptable salts thereof, and (b) a pharmaceutically acceptable carrier.
  • the compounds of structural formulae I, Ia and Ib may be used in pharmaceutical compositions in which the compound of structural formula I, Ia or Ib or a pharmaceutically acceptable salt thereof is the only active ingredient.
  • the compounds of structural formulae I, Ia and Ib may also be used in pharmaceutical compositions that include one or more other active pharmaceutical ingredients.
  • composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions described hereinencompass any composition made by admixing a compound of structural formula I, Ia, or Ib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • Compounds of structural formulae I, Ia and Ib may be used in combination with other drugs that may also be useful in the treatment or amelioration of the diseases or conditions for which compounds of structural formulae I, Ia and Ib are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of structural formula I, Ia or Ib. In the treatment of patients who suffer from chronic inflammatory conditions, more than one drug may be administered.
  • the compounds of structural formulae I, Ia and Ib may generally be administered to a patient who is already taking one or more other drugs for these conditions. Often the compounds will be administered to a patient who is already being treated with one or more anti-pain compounds when the patient’s pain is not adequately responding to treatment.
  • the combination therapy also includes therapies in which the compound of structural formula I, Ia or Ib and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compound of structural formula I, Ia or Ib and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present disclosure include those that contain one or more other active ingredients, in addition to a compound of structural formula I, Ia or Ib.
  • Examples of other active ingredients that may be administered in combination with a compound of structural formula I, Ia or Ib , and either administered separately or in the same pharmaceutical composition include but are not limited to: (i) anti-steatotic agents; (ii) anti-inflammatory agents; (iii) immunooncology agent; (iv) lipid-lowering agents; (v) cholesterol lowering agents; 25602 (vi) glucose-lowering agents, including SGLT2 inhibitors; (vii) anti-neovascular agents; (viii) nonsteroidal anti-inflammatory drugs ("NSAIDs"); (ix) acetyl-salicylic acid drugs (ASA) including aspirin; paracetamol; (x) regenerative therapy treatments; (xi) checkpoint inhibitors including anti-PD1 and anti-PDL1 inhibitors; (xii) checkpoint inhibitors including anti-PD1 and anti-PDL1 inhibitors; (xii) checkpoint inhibitors including anti-PD1 and anti-PDL1 inhibitors; (xii) checkpoint inhibitors including
  • the pharmaceutical composition comprises: (1) a compound of structural formula I, Ia or Ib, or a pharmaceutically acceptable salt thereof; (2) one or more compounds, or pharmaceutically acceptable salts thereof, selected from the group: (i) anti-steatotic agents; (ii) anti-inflammatory agents; (iii) immunooncology agent; (iv) lipid-lowering agents; (v) cholesterol lowering agents; (vii) glucose-lowering agents, including SGLT2 inhibitors; (vii) anti-neovascular agents; (viii) nonsteroidal anti-inflammatory drugs ("NSAIDs"); (ix) acetyl-salicylic acid drugs (ASA) including aspirin; paracetamol; (x) regenerative therapy treatments; (xi) checkpoint inhibitors including anti-PD1 and anti-PDL1 inhibitors; (xii) chemotherapy procedures; (xiii) radiation therapy; (xiv) surgical procedures; (xv) urate-lowering therapy; (xvi) anabolics and cartilage regenerative therapy;
  • anti-steatotic agents including but not limited to, DGAT2 inhibitors.
  • Suitable anti-inflammatory agents include, but are not limited to, TNF ⁇ inhibitors, JAK inhibitors and NSAIDs.
  • Suitable lipid-lowering agents include, but are not limited to statins and PCSK9.
  • Suitable immunooncology agents include, but are not limited to, PD-L1 inhibitors and PD-1 inhibitors and STING antagonists.
  • Suitable glucose-lowering agents include, but are not limited to, insulin, SGLT2 inhibitors, metformin, GLP1-agonists.
  • Suitable anti-neovascular agents include, but are not limited to, anti-VEG-F treatment.
  • Suitable NSAIDs or non-steroidal anti-inflammatory drugs include, but are not limited to, aspirin, diclofenac, diflunisal, etodolac, fenoprofin, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, meloxicam, naproxen, naproxen sodium, oxaprozin, piroxicam, sulindac, and tolmetin.
  • Suitable analgesics include, but are not limited to, acetaminophen and duloxetine.
  • the above combinations include combinations of a compound of structural formula I, Ia or Ib or a pharmaceutically acceptable salt thereof not only with one other active compound, but also with two or more other active compounds.
  • Non-limiting examples include combinations of compounds with two or more active compounds selected from: anti-steatotic agents, anti-inflammatory agents, lipid-lowering agents, anti-fibrosis, immunooncology agents, glucose- lowering agents and anti-neovascular agents, NSAIDs (non-steroidal anti-inflammatory drugs), and an analgesics.
  • a method for the treatment or prevention of a NLRP3 mediated disease, disorder or condition comprises administration to a patient in need of such treatment or at risk of developing a NLRP3 mediated disease with a therapeutically effective amount of a NLRP3 inhibitor and an amount of one or more active ingredients, such that together they give effective relief.
  • a pharmaceutical composition comprising a NLRP3 inhibitor and one or more active ingredients, together with at least one pharmaceutically acceptable carrier or excipient.
  • a product comprising a NLRP3 inhibitor and one or more active ingredients as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of an NLRP3-mediated disease, disorder or condition.
  • a combined preparation may be, for example, in the form of a twin pack.
  • a compound of structural formula I, Ia or Ib may be used in conjunction with another pharmaceutical agent effective to treat that disease, disorder or conditon.
  • a method for the treatment or prevention of chronic inflammatory conditions comprises administration to a patient in need of such treatment an amount of a compound structural formula I, Ia, or Ib or a pharmaceutically acceptable salt thereof and an amount of another pharmaceutical agent effective to threat that disorder, disease or condition, such that together they give effective relief.
  • a method for the treatment or prevention of chronic inflammatory conditions comprises administration to a patient in need of such treatment an amount of a compound structural formula I, Ia, or Ib ora pharmaceutically acceptable salt thereof and an amount of another pharmaceutical agent useful in treating that particular condition, disorder or disease, such that together they give effective relief.
  • terapéuticaally effective amount means the amount the compound of structural formula I (or Ia or Ib) that will elicit the biological or medical response of a cell, tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disorder being treated.
  • the novel methods of treatment disclosed herein are for disorders known to those skilled in the art.
  • the term “mammal” includes humans, and companion animals such as dogs and cats.
  • the weight ratio of the compound of the Formula I to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
  • the weight ratio of the compound of the Formula I generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200.
  • Combinations of a compound of the Formula I and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
  • LC/MS determinations were carried out on Waters ACQUITY UPLC equipped with a DAD and QDa MS detectors using the following conditions: Waters ACQUITY UPLC BEH C18 1.7mm 2.1x50mm column using mobile phase containing A: 0.1% TFA in water and B: 0.1% TFA in acetonitrile with a gradient from 10% B to 90% B over 2.0 min and hold at 90%B for 0.4 min at a flow rate of 0.5 mL/min.
  • Proton or 1 H NMR was acquired using a Bruker 500 MHz NEO NMR spectrometer equipped with a 5mm iProbe in accordance with standard analytical techniques, unless specified otherwise, and results of spectral analysis arereported.
  • DFMS Bis(((difluoromethyl)-sulfinyl)oxy)zinc
  • DIC N,N′-diisopropyl-carbodiimide
  • DAST diethylaminosulfur trifluoride
  • DCE dichloroethane
  • DCM dichloromethane
  • dd is doublet of doublets
  • DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
  • Dess-Martin Periodinane is 1,1,1- tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one
  • dqd is doublet of a quartet of doublets
  • DEA diethanolamine
  • DIPEA is N,N-diisopropylethylamine
  • DMA is dimethyl-acetamide
  • DMAP dimethylamino pyridine
  • DME dimethoxyethane
  • Scheme B Scheme B amines, such as B-3, from Boc-protected amines, such as B-1. Reductive amination of free amine B-1 followed by Boc deprotection affords selectively substituted amine derivatives such as B-3. 25602 Scheme C as C-4.
  • SNAr regioselective nucleophilic aromatic substitution
  • Step 2 2-Iodo-3-methyl-5-(trifluoromethyl)phenol: NaH (128.5 g, 3.21 mol, 60 wt%) was added at 0 o C to a stirring solution of 3-methyl-5-(trifluoromethyl)phenol (283 g, 1.61 mol) in toluene (1.42 L) under N2 atmosphere. The resulting mixture was stirred at 0°C for 30 min, followed by the portion wise addition of a solution of I 2 (306.1 g, 1.21 mmol) in toluene (5.66 L). The resulting mixture was stirred at 20 °C for 3 h, then quenched by pouring onto a water/ice bath. The mixture was diluted with EtOAc, and the layers were separated.
  • Step 3 1-(Ethoxymethoxy)-2-iodo-3-methyl-5-(trifluoromethyl)benzene: Chloromethyl ethyl ether (289.9 g, 3.07 mol) was added at 0 o C to a stirring solution of 2-iodo-3-methyl-5- (trifluoromethyl)phenol (463 g, 1.53 mol) and Cs2CO3 (998.9 g, 3.07 mmol) in DMF (4.6 L) under a N 2 atmosphere.
  • Step 4 2-(2-(Ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane: A mixture containing 1-(ethoxymethoxy)-2-iodo-3-methyl-5- (trifluoromethyl)benzene (330 g, 916.4 mmol), B 2 pin 2 (469.1 g, 3.67 mol), Et 3 N (556.4 g, 5.50 mol), Pd(OAc)2 (10.3 g, 45.8 mmol), and (2-biphenyl)dicyclohexylphosphine (32.1 g, 91.6 mmol) in 1,4-dioxane (3.3 L) was placed under N 2 atmosphere.
  • the reaction mixture was stirred for 6 h at 100 o C, then cooled to 25 o C and quenched with ice water. The resulting mixture was filtered, and the solid residue was washed with EtOAc. The filtrate layers were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The resulting crude residue was purified by silica gel chromatography (EtOAc:petroleum ether) and the solvent was removed under vacuum. The resulting solid was dissolved in hexanes and stirred for 5 min at –30 o C. Then the precipitated solids were collected 25602 by filtration to afford the title compound.
  • Step 2 tert-butyl (3aS,7R,7aR and 3aR,7S,7aS)-7-hydroxyoctahydro-1H-indole-1-carboxylate: To a solution of tert-butyl (3aS,7aR and 3aR,7aS)-7-oxooctahydro-1H-indole-1-carboxylate (240 mg, 1 mmol) in MeOH (5 mL) at 0 °C was added NaBH4 (190 mg, 5 mmol). The mixture was warmed to room temperature and stirred for 2 h. The solvent was removed under reduced pressure, and the resulting crude residue was diluted with EtOAc and H 2 O.
  • reaction mixture was heated to 100 °C and stirred for 12 h. Then the reaction mixture was allowed to cool to room temperature, and diluted with H 2 O and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (x3). Combined organic layers were dried over MgSO 4 , filtered and the solvent was removed under reduced pressure. The resulting crude residue was purified by silica gel chromatography (EtOAc:hexanes) to afford a racemic mixture of the title compounds.
  • the reaction mixture was warmed to room temperature and stirred for 2 h. Then the reaction was quenched with a saturated solution of NH 4 Cl, and diluted with H 2 O and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (x3). The combined organic layers were dried over MgSO 4 , filtered and the solvent was removed under vacuum. The resulting residue was dissolved in THF (1.0 mL), and a solution of DDQ (1 mL, 0.2 mmol, 0.2 M in THF) was added. The reaction mixture was stirred at room temperature for 12 h.
  • the reaction mixture was heated to 25602 50°C and stirred for 16 h, followed by cooling to room temperature.
  • the resulting crude mixture filtered, and purified by reverse phase HPLC (C18 stationary phase, MeCN/H2O + 0.1% TFA).
  • the product fractions were combined, diluted with EtOAc and basified with saturated NaHCO 3 solution.
  • the layers were separated, and the aqueous layer was extracted with EtOAc (x3).
  • the combined organic layers were dried over MgSO4, filtered, and solvents removed under reduced pressure to afford the title compound.
  • reaction mixture was cooled to –78 o C, followed by addition of AcOH (9.4 mL, 165 mmol) and H 2 O 2 (3.83 mL, 165 mmol) over 15 min, then warmed to room temperature and stirred for 12 h.
  • the reaction mixture was then diluted with a saturated aqueous NH4Cl, a saturated aqueous solution of Na 2 SO 3 , H 2 O, and DCM.
  • the layers were separated and the aqueous phase was extracted with DCM (x2).
  • the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
  • the resulting crude residue was purified by silica gel chromatography (EtOAc:petroleum ether) to afford the title compound.
  • Step 2 1-bromo-2-(ethoxymethoxy)-3-fluoro-4-(trifluoromethyl)benzene: To a solution of 6- bromo-2-fluoro-3-(trifluoromethyl)phenol (7.9 g, 30.5 mmol) in DMF (70 mL), were added (chloromethoxy)ethane (4.24 mL, 45.8 mmol) and Cs 2 CO 3 (14.9 g, 45.8 mmol).
  • Step 3 2-(2-(ethoxymethoxy)-3-fluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane: To a solution of 2-bromo-3-(ethoxymethoxy)-4-fluoro-1-methyl-5- (trifluoromethyl)benzene (300 mg, 0.91 mmol) in 1,4-dioxane (8 mL) were added 4,4,5,5- tetramethyl-1,3,2-dioxaborolane (0.53 mL, 3.6 mmol), Et3N (0.71 mL, 5.4 mmol), Pd(OAc)2 (10.2 mg, 0.045 mmol), and 2-(dicyclohexylphosphino)biphenyl (31.8 mg, 0.091 mmol).
  • Step 2 2-(2-methoxy-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane: To a solution of 2-iodo-1-methoxy-3-methyl-5-(trifluoromethyl)benzene (1.5 g, 4.75 mmol) in 1,4-dioxane (12 mL) were added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.43 g, 19.0 mmol), Et3N (4.0 mL, 28.5 mmol), Pd(OAc)2 (107 mg, 0.48 mmol), and 2- (dicyclohexylphosphino)biphenyl (333 mg, 0.95 mmol).
  • Step 3 (2-methoxy-6-methyl-4-(trifluoromethyl)phenyl)boronic acid: NH4OAc (1.23 g, 15.9 mmol) and NaIO4 (3.41 g, 15.9 mmol) was added to a solution of 2-(2-methoxy-6-methyl-4- (trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.26 g, 3.99 mmol) in acetone (5 mL) and water (5 mL). The resulting reaction mixture was stirred at room temperature for 12 h. Then the reaction mixture was diluted with H 2 O and EtOAc.
  • Step 2 tert-butyl 5-methoxy-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate: Pd/C (34.3 mg, 0.32 mmol) was added to a solution of tert-butyl 5-methoxy-1H-pyrrolo[2,3-c]pyridine-1- carboxylate (400 mg, 1.6 mmol) in MeOH (10 mL). The reaction mixture was stirred at 70 °C for 16 h under H2 (15 psi).
  • Step 4 (3aR,7aR)-octahydro-5H-pyrrolo[2,3-c]pyridin-5-one and (3aS,7aS)-octahydro-5H- pyrrolo[2,3-c]pyridin-5-one: PtO 2 (105 mg, 0.46 mmol) was added to a solution of 2,3-dihydro- 25602 1H-pyrrolo[2,3-c]pyridin-5-ol (210 mg, 1.5 mmol) in AcOH (10 mL).
  • Step 2 5-chloro-2-(5-methyl-3-((3aS,7aR)-6-methyloctahydro-1H-pyrrolo[2,3-c]pyridin-1-yl)- 1,2,4-triazin-6-yl)phenol: HCl 0.92 mmol, 4 M in 1,4-dioxane) was added to a solution of (3aS,7aR)-1-(6-(4-chloro-2- phenyl)-5-methyl-1,2,4-triazin-3-yl)-6- methyloctahydro-1H-pyrrolo[2,3-c]pyridine (37 mg, 0.09 mmol) in 1,4-dioxane (0.92 mL).
  • the mixture was degassed with N2 for 10 min and stirred at 100 °C for 15 h. Then additional cyclopropylboronic acid (24 mg, 0.28 mmol), tricyclohexyl- phosphine (52 mg, 0.19 mmol), and Pd(OAc)2 (4.2 mg, 0.02 mmol) were added.
  • the reaction degassed with N2 and stirred at 100 °C for 8 h. Then the reaction mixture was cooled to room temperature and diluted with H2O and EtOAc. The layers were separated, and the aqeuous layer extracted with EtOAc (x3).
  • Example 72 2-(3-((3aS,7aR)-6-ethyloctahydro-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-methyl-1,2,4-triazin-6-yl)-5- (trifluoromethyl)phenol
  • 2-(5-methyl-3-( [2,3-c]pyridin-1-yl)-1,2,4- triazin-6-yl)-5-(trifluoromethyl) mg, 0.1 mmol) in MeOH (1 mL) at 0 °C was added acetaldehyde (60 ⁇ L, 1.0 mmol), followed by NaBH(OAc) 3 (64 mg, 0.3 mmol).
  • Examples 73 and 74 3-methyl-2-(3-((3aS,7aR or 3aR,7aS)-6-methyloctahydro-1H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4- yl)-5-(trifluoromethyl)phenol (Example 73, Peak 1), and 3-methyl-2- or 3aS,7aR)-6-methyloctahydro-1H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4- 6-yl)-5-(trifluoromethyl)phenol (Example 74, Peak 2)
  • reaction mixture was warmed up to room temperature and stirred for 2 h. Then the solvent was were removed under reduced pressure and crude mixture was purified by reverse phase HPLC (C18 stationary phase, MeCN/H 2 O + 0.1% TFA) to afford the racemic 25602 mixture of the title compounds.
  • Example Structure Name LCMS Chiral [M+H] + Method a e . e o owng compoun was prepare usng a proceure sm ar o e proceure or Example 67 using the appropriate starting materials.
  • reaction mixture was then cooled to 0 °C and quenched by the dropwise addition of saturated aqueous NaHCO3.
  • the resulting mixture was diluted with DCM, the layers separated and the aqueous phase was extracted with DCM (x2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
  • the resulting crude residue was purified by silica gel chromatography (EtOAc:petroleum ether) to afford the title compound.
  • Step 2 (3aS,7aR and 3aR,7aS)-1-(6-(4-(1,1-difluoroethyl)-2-methoxyphenyl)-5-methyl-1,2,4- triazin-3-yl)-6-methyloctahydro-1H-pyrrolo[2,3-c]pyridine: A solution of 2,2'-bipyridine (11.8 mg, 0.076 mmol) and NiCl2DME (16.6 mg, 0.076 mmol) in DMA (1 mL) was stirred at 50 °C for 30 min under a N 2 atmosphere.
  • reaction mixture was then heated to 140 °C, and stirred for 2 h. Then the reaction mixture was cooled to room temperature, and diluted with H2O and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (x2). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The resulting crude residue was purified by reverse phase HPLC (C18 stationary phase, MeCN/H 2 O + 0.05% NH 4 OH + 10mM NH 4 HCO 3 ) to afford the racemic mixture of the title compounds.
  • a 100 mg potency tablet is composed of 100 mg of any one of the Examples, 268 mg microcrystalline cellulose, 20 mg of croscarmellose sodium, and 4 mg of magnesium stearate. The active, microcrystalline cellulose, and croscarmellose are blended first. The mixture is then lubricated by magnesium stearate and pressed into tablets. BIOLOGICAL ASSAY 25602 Activation of the canonical NLRP3 inflammasome requires two steps, priming and activation.
  • a priming signal such as a pathogen activated molecular patterns (PAMPs) or danger- activated molecular patterns (DAMPs) are recognized by Toll-like receptors leads to nuclear factor kappa B (NF-KB)-mediated signaling. This in turn, up-regulates transcription of inflammasome-related components, including inactive NLRP3 and prolL-1 ⁇ (Bauernfeind et al., J. Immunol.2009, 183, 787 - 791; Franchi et al., Nat. Immunol.2012, 13, 325 - 332; Franchi et al., J. Immunol.2014, 193, 4214 - 4222).
  • PAMPs pathogen activated molecular patterns
  • DAMPs danger- activated molecular patterns
  • the second step is activation which induces oligomerization of NLRP3 and subsequent assembly of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and procaspase-1 into an inflammasome complex.
  • ASC apoptosis-associated speck-like protein containing a CARD
  • procaspase-1 into an inflammasome complex.
  • This triggers the transformation of procaspase-1 to caspase-1, and the production and secretion of mature IL-1 ⁇ and IL-18 (Kim et al., J. Inflamm.2015, 12, 41; Ozaki et al., J. Inflamm. Res.2015, 8, 15 - 27; Rabeony et al., Eur. J. Immunol.2015, 45, 2847).
  • ASC SPECK an event commonly referred to as “ASC SPECK” formation as it is identified in the cell as a discrete puncta within the cell after staining and visualization of ASC using common immunocytochemical methods.
  • ASC SPECK an event commonly referred to as “ASC SPECK” formation as it is identified in the cell as a discrete puncta within the cell after staining and visualization of ASC using common immunocytochemical methods.
  • the ability of compounds to inhibit NLRP3 inflammasome activation was determined in vitro by monitoring formation of the ASC-SPECK in human monocytic THP-1 cells after stimulation.
  • THP-1 cells (ATCC catalog #TIB-202) were maintained in complete growth media containing Roswell Park Memorial Institute RPMI (ATCC catalog #30-2001), 10% heat inactivated fetal bovine serum, 1X penicillin/streptomycin and 0.05mM 2-mercaptoethanol.
  • undifferentiated THP-1 cells were plated at a density of 20,000 cells per well in a 384-well plate (Poly-D-lysine coated Cell Carrier Ultra microplate, Perkin Elmer catalog #6057500) in complete growth media supplemented with 10 ng/ml phorbol 12-myristate 13-acetate (PMA; Sigma catalog #P8139), and then incubated overnight. The next day, media was replaced with assay media [RPMI (Gibco catalog #11875-093), 0.01% bovine serum albumin (BSA)].
  • PMA phorbol 12-myristate 13-acetate
  • Cells 25602 were first permeabilized with 0.3% Triton X-100 in phosphate-buffered saline (PBS) for 15 minutes and then incubated in blocking buffer containing 5% goat serum, 0.3% tween-20 and 0.03% sodium azide in PBS for 1 hour. Cells were stained with a mixture of ASC-Alexa 488 antibody (diluted 1:200 in blocking buffer) and nuclear stain DRAQ5 (1:5000 in blocking buffer, Thermo catalog #62251) in blocking buffer for 1 hour. Following a wash with 0.3% Tween-20 in PBS, plates were imaged with an Opera Phenix High Content Screening System. The number of DRAQ5 positive cells containing ASC SPECKS were quantified in each well.
  • PBS phosphate-buffered saline
  • EC 50 values were calculated by standard curve-fitting analysis using an internally developed program in TIBCO Spotfire software.
  • the compounds of structural formula I inhibit NLRP3 inflammasome activation in the above Biological Assay and have EC50 values of less than 5 micromolar.
  • Specific EC50 values of the compounds of Examples 1-106 in the above Biological Assay are listed in Table I. Table I.
  • effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in responsiveness of the mammal being treated for any of the indications with the compounds of structural formulae I, Ia, Ib and pharmaceutically acceptable salts thereof.
  • the specific pharmacological responses observed may vary according to and depending upon the particular compounds selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present disclosure. It should be understood that various alternatives to the embodiments of the present disclosure described herein may be employed in practicing the methods and uses disclosed herein. .

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Abstract

De nouveaux composés de formule structurale I, et leurs sels pharmaceutiquement acceptables, sont des inhibiteurs de NLRP3 et peuvent être utiles dans le traitement, la prévention, la gestion, le soulagement, le contrôle et la suppression de maladies médiées par NLPR3. Ces composés peuvent être utiles dans le traitement, la prévention ou la gestion de maladies, de troubles et d'états médiés par NLRP3 tels que, mais de façon non limitative, la goutte, la pseudo-goutte, le CAPS, la fibrose NASH, l'insuffisance cardiaque, la péricardite idiopathique, la dermatite atopique, la maladie intestinale inflammatoire, la maladie d'Alzheimer, la maladie de Parkinson et la lésion cérébrale traumatique.
PCT/US2023/077986 2022-11-02 2023-10-27 Triazines utiles comme inhibiteurs de la protéine réceptrice de type nod 3 WO2024097598A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070207985A1 (en) * 2006-03-01 2007-09-06 Bristol-Myers Squibb Company Triazine 11-beta hydroxysteroid dehydrogenase type 1 inhibitors
WO2013092244A1 (fr) * 2011-12-20 2013-06-27 Basf Se Triazines herbicides
WO2019141552A1 (fr) * 2018-01-18 2019-07-25 Basf Se Composés herbicides de triazine
WO2019191229A1 (fr) * 2018-03-27 2019-10-03 Ptc Therapeutics, Inc. Composés permettant de traiter la maladie de huntington
WO2020234715A1 (fr) * 2019-05-17 2020-11-26 Novartis Ag Inhibiteurs d'inflammasome nlrp3

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070207985A1 (en) * 2006-03-01 2007-09-06 Bristol-Myers Squibb Company Triazine 11-beta hydroxysteroid dehydrogenase type 1 inhibitors
WO2013092244A1 (fr) * 2011-12-20 2013-06-27 Basf Se Triazines herbicides
WO2019141552A1 (fr) * 2018-01-18 2019-07-25 Basf Se Composés herbicides de triazine
WO2019191229A1 (fr) * 2018-03-27 2019-10-03 Ptc Therapeutics, Inc. Composés permettant de traiter la maladie de huntington
WO2020234715A1 (fr) * 2019-05-17 2020-11-26 Novartis Ag Inhibiteurs d'inflammasome nlrp3

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Title
DATABASE PUBCHEM COMPOUND 19 May 2008 (2008-05-19), ANONYMOUS: "3-Cyclopropyl-5-methyl-6-phenyl-1,2,4-triazine", XP093172019, Database accession no. 24784897 *

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